Benzoimidazole compounds

ABSTRACT

Benzoimidazole compounds, compositions, and methods of using them in leukocyte recruitment inhibition, in modulating H 4  receptor, and in treating conditions such as inflammation, H 4  receptor-mediated conditions, and related conditions.

This application is a divisional of U.S. patent application Ser. No.10/952,989, filed on Sep. 29, 2004 now U.S. Pat. No. 7,432,378, which inturn claims the benefit of U.S. provisional patent application Ser. No.60/507,236, filed on Sep. 30, 2003 each of which is incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

The invention relates to novel, pharmaceutically active, fusedheterocyclic compounds, more particularly benzoimidazole compounds, andmethods of using them to treat or prevent disorders and conditionsmediated by the histamine H₄ receptor.

BACKGROUND OF THE INVENTION

Histamine was first identified as a hormone (G. Barger and H. H. Dale,J. Physiol. (London) 1910, 41:19-59) and has since been demonstrated toplay a major role in a variety of physiological processes, including theinflammatory “triple response” via H₁ receptors (A. S. F. Ash and H. O,Schild, Br. J. Pharmac. Chemother. 1966, 27:427-439), gastric acidsecretion via H₂ receptors (J. W. Black et al., Nature 1972,236:385-390), and neurotransmitter release in the central nervous systemvia H₃ receptors (J.-M. Arrang et al., Nature 1983, 302:832-837) (forreview see S. J. Hill et al., Pharmacol. Rev. 1997, 49(3):253-278). Allthree histamine receptor subtypes have been demonstrated to be membersof the superfamily of G protein-coupled receptors (I. Gantz et al.,Proc. Natl. Acad. Sci. U.S.A. 1991, 88:429-433; T. W. Lovenberg et al.,Mol. Pharmacol. 1999, 55(6):1101-1107; M. Yamashita et al. Proc. Natl.Acad. Sci. U.S.A. 1991, 88:11515-11519). There are, however, additionalfunctions of histamine that have been reported, for which no receptorhas been identified. For example, in 1994, Raible et al., demonstratedthat histamine and R-α-methylhistamine could activate calciummobilization in human eosinophils (D. G. Raible et al., Am. J. Respir.Crit. Care Med. 1994, 149:1506-1511). These responses were blocked bythe H₃-receptor antagonist thioperamide. However, R-α-methylhistaminewas significantly less potent than histamine, which was not consistentwith the involvement of known H₃ receptor subtypes. Therefore, Raible etal. hypothesized the existence of a novel histamine receptor oneosinophils that was non-H₁, non-H₂, and non-H₃. Most recently severalgroups (T. Oda et al., J. Biol. Chem. 2000, 275(47):36781-36786; C. Liuet al., Mol. Pharmacol. 2001, 59(3):420-426; T. Nguyen et al., Mol.Pharmacol. 2001, 59(3):427-433; Y. Zhu et al., Mol. Pharmacol. 2001,59(3):434-441; K. L. Morse et al., J. Pharmacol. Exp. Ther. 2001,296(3):1058-1066) have identified and characterized a fourth histaminereceptor subtype, the H₄ receptor. This receptor is a 390 amino acid,seven-transmembrane, G protein-coupled receptor with approximately 40%homology to the histamine H₃ receptor. In contrast to the H₃ receptor,which is primarily located in the brain, the H₄ receptor is expressed atgreater levels in eosinophils and mast cells, among other cells, asreported by Liu et al. (see above) and C. L. Hofstra et al. (J.Pharmacol. Exp. Ther. 2003, 305(3):1212-1221). Because of itspreferential expression on immunocompetent cells, this H₄ receptor isclosely related with the regulatory functions of histamine during theimmune response.

A biological activity of histamine in the context of immunology andautoimmune diseases is closely related with the allergic response andits deleterious effects, such as inflammation. Events that elicit theinflammatory response include physical stimulation (including trauma),chemical stimulation, infection, and invasion by a foreign body. Theinflammatory response is characterized by pain, increased temperature,redness, swelling, reduced function, or a combination of these.

Mast-cell de-granulation (exocytosis) releases histamine and leads to aninflammatory response that may be initially characterized by ahistamine-modulated wheal and flare reaction. A wide variety ofimmunological stimuli (e.g., allergens or antibodies) andnon-immunological (e.g., chemical) stimuli may cause the activation,recruitment, and de-granulation of mast cells. Mast-cell activationinitiates allergic (H₁) inflammatory responses, which in turn cause therecruitment of other effector cells that further contribute to theinflammatory response. The histamine H₂ receptors modulate gastric acidsecretion, and the histamine H₃ receptors affect neurotransmitterrelease in the central nervous system.

Modulation of H₄ receptors controls the release of inflammatorymediators and inhibits leukocyte recruitment, thus providing the abilityto prevent and/or treat H₄-mediated diseases and conditions, includingthe deleterious effects of allergic responses such as inflammation.Compounds according to the present invention have H₄ receptor modulatingproperties. Compounds according to the present invention have leukocyterecruitment inhibiting properties. Compounds according to the presentinvention have anti-inflammatory properties.

Examples of textbooks on the subject of inflammation include J. I.Gallin and R. Snyderman, Inflammation: Basic Principles and ClinicalCorrelates, 3^(rd) Edition, (Lippincott Williams & Wilkins,Philadelphia, 1999); V. Stvrtinova, J. Jakubovsky and I. Hulin,“Inflammation and Fever”, Pathophysiology Principles of Diseases(Textbook for Medical Students, Academic Press, 1995); Cecil et al.,Textbook Of Medicine, 18^(th) Edition (W.B. Saunders Company, 1988); andSteadmans Medical Dictionary.

Background and review material on inflammation and conditions relatedwith inflammation can be found in articles such as the following: C.Nathan, Points of control in inflammation, Nature 2002, 420:846-852; K.J. Tracey, The inflammatory reflex, Nature 2002, 420:853-859; L. M.Coussens and Z. Werb, Inflammation and cancer, Nature 2002, 420:860-867;P. Libby, Inflammation in atherosclerosis, Nature 2002, 420:868-874; C.Benoist and D. Mathis, Mast cells in autoimmune disease, Nature 2002,420:875-878; H. L. Weiner and D. J. Selkoe, Inflammation and therapeuticvaccination in CNS diseases, Nature 2002, 420:879-884; J. Cohen, Theimmunopathogenesis of sepsis, Nature 2002, 420:885-891; D. Steinberg,Atherogenesis in perspective: Hypercholesterolemia and inflammation aspartners in crime, Nature Medicine 2002, 8(11):1211-1217.

Inflammation herein refers to the response that develops as aconsequence of histamine release, which in turn is caused by at leastone stimulus. Examples of such stimuli are immunological stimuli andnon-immunological stimuli.

Inflammation is due to any one of a plurality of conditions such asallergy, asthma, chronic obstructed pulmonary disease (COPD),atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatorybowel diseases (including Crohn's disease and ulcerative colitis),psoriasis, allergic rhinitis, scleroderma, autoimmune thyroid diseases,immune-mediated (also known as type 1) diabetes mellitus and lupus,which are characterized by excessive or prolonged inflammation at somestage of the disease. Other autoimmune diseases that lead toinflammation include Myasthenia gravis, autoimmune neuropathies, such asGuillain-Barré, autoimmune uveitis, autoimmune hemolytic anemia,pernicious anemia, autoimmune thrombocytopenia, temporal arteritis,anti-phospholipid syndrome, vasculitides, such as Wegener'sgranulomatosis, Behcet's disease, dermatitis herpetiformis, pemphigusvulgaris, vitiligio, primary biliary cirrhosis, autoimmune hepatitis,autoimmune oophoritis and orchitis, autoimmune disease of the adrenalgland, polymyositis, dermatomyositis, spondyloarthropathies, such asankylosing spondylitis, and Sjogren's syndrome. Regarding the onset andevolution of inflammation, inflammatory diseases orinflammation-mediated diseases or conditions include, but are notlimited to, acute inflammation, allergic inflammation, and chronicinflammation.

Cited references are incorporated herein by reference.

SUMMARY OF THE INVENTION

The invention features a compound of formula (I) or (II):

wherein

-   W is, independently from other member and substituent assignments, N    or CR⁷;-   X is, independently from other member and substituent assignments, N    or CH;-   Y is, independently from other member and substituent assignments,    O, NR¹², or CR¹²R¹³;-   Z is, independently from other member and substituent assignments, N    or CR¹⁴, in which case the solid/dash feature (    ) in any one of formulae (I) and (II) is a single bond; or Z is C,    in which case the solid/dash feature (    ) in any one of formulae (I) and (II) is a double bond;-   n is, independently from member and substituent assignments, 0, 1,    or 2;-   each of R¹⁻⁴ is, independently from other member and substituent    assignments, H, C₁₋₄alkyl, C₂₋₅alkenyl, C₂₋₅alkynyl, C₃₋₆cycloalkyl,    —C₁₋₄alkoxy, —C₁₋₄alkylamino, —C₁₋₄alkylthio, —C₁₋₄alkylsulfonyl,    —OC₃₋₆cycloalkyl, —OCH₂Ph, cyano, —CF₃, F, Cl, Br, I, nitro, —OCF₃,    —SCF₃, —OR^(c), —SR^(c), —S(O)R^(c), —SO₂R^(c), —C(O)R^(c), phenyl,    benzyl, phenethyl, —C(O)NR^(a)R^(b), —C(O)OR^(c), —NR^(a)R^(b),    —CH₂NR^(a)R^(b) or —CH₂OR^(c); wherein each of R^(a), R^(b) and    R^(c) is, independently from other substituent assignments, selected    from H, C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl,    (C₃₋₆cycloalkyl)C₁₋₂alkyl-, benzyl and phenethyl, or R^(a) and R^(b)    taken together with the nitrogen to which they are attached, form a    4-7 membered heterocyclic ring HetCyc1, wherein said ring HetCyc1    has 0 or 1 additional heteroatoms selected from O, S, >NH and    >NC₁₋₆alkyl, and wherein any phenyl, phenethyl, benzyl, alkyl or    cycloalkyl moiety in any of said R¹⁻⁴, R^(a), R^(b), R^(c), and said    ring HetCyc1 is optionally, and independently from other substituent    assignments, substituted with 1, 2 or 3 substituents selected from    C₁₋₃alkyl, halo, hydroxy, amino, and C₁₋₃alkoxy;-   each of R⁵⁻⁷ is, independently from other member and substituent    assignments, H, C₁₋₆alkyl, F, Cl, Br, I, CF₃, —OCF₃, —OR^(c),    —C₁₋₃alkylOR^(c), —C₁₋₃alkylSR^(c), —SR^(c), —S(O)R^(c), —SO₂R^(c),    C₁₋₄alkoxy, cyano, nitro, —C(O)NR^(a)R^(b), —NR^(a)R^(b),    —C₁₋₃alkylNR^(a)R^(b), —C(O)phenyl, —C(O)C₁₋₁₆alkyl, —S(O)C₁₋₄alkyl,    or —SO₂C₁₋₄alkyl; or, R⁵ and R⁶ for a compound of formula (I) taken    together with the carbon atoms to which they are attached form a    cyclic structure Cyc1 selected from aryl, heteroaryl, 5- or    6-membered carbocycle, and 5- or 6-membered heterocycle with 1 or 2    heteroatoms, wherein said cyclic structure Cyc1 is, independently    from other substituent assignments, substituted with 0, 1, or 2    substituents selected from C₁₋₃alkyl, halo, hydroxy, amino, and    C₁₋₃alkoxy; or, R⁷ and R⁶ for a compound of formula (II) taken    together with the carbon atoms to which they are attached form a    cyclic structure Cyc2 selected from aryl, heteroaryl, 5- or    6-membered carbocycle, and 5- or 6-membered heterocycle with 1 or 2    heteroatoms, wherein said cyclic structure Cyc2 is, independently    from other substituent assignments, substituted with 0, 1, or 2    substituents selected from C₁₋₃alkyl, halo, hydroxy, amino, and    C₁₋₃alkoxy;-   R⁸ is, independently from other member and substituent assignments,    H, C₁₋₆alkyl, C₁₋₄alkoxy, or OH;-   each of R⁹ and R¹⁰ is, independently from other member and    substituent assignments, H or C₁₋₆alkyl, or R⁹ and R¹⁰ taken    together form a 5-6 membered cyclic structure Cyc3, wherein said    cyclic structure Cyc3 is a 5- or 6-membered carbocycle or a 5- or    6-membered heterocycle with 1 or 2 heteroatoms, and wherein said    cyclic structure Cyc3 is, independently from other substituent    assignments, substituted with 0, 1, or 2 substituents selected from    C₁₋₃alkyl, halo, hydroxy, amino, and C₁₋₃alkoxy;-   R¹¹ is, independently from other member and substituent assignments,    H or C₁₋₄alkyl;-   each of R¹² and R¹³ is, independently from other member and    substituent assignments, H or C₁₋₄alkyl; or, when Y is CR¹²R¹³, R¹²    and R¹³ taken together with the carbon member to which they are    attached form an optionally substituted cyclic structure Cyc4,    wherein said cyclic structure Cyc4 is a 3- to 6-membered carbocycle    or a 3- to 6-membered heterocycle with 0 or 1 additional    heteroatoms, or CR¹²R¹³ is C═O;-   R¹⁴ is, independently from other member and substituent assignments,    H, C₁₋₄alkyl, OH, or C₁₋₄alkoxy;    an enantiomer, diastereomer, racemate thereof, or a pharmaceutically    acceptable salt, amide or ester thereof;    with the following provisos:    when Y is O or NR¹², then Z is CR¹⁴ and R⁸ is not OH or C₁₋₄alkoxy;    when Z is N, Y is CR¹²R¹³; and    none of R¹⁻⁴ is C(O)NH₂.

Isomeric forms of the compounds of formulae (I) and (II), and of theirpharmaceutically acceptable salts, amides and esters, are encompassedwithin the present invention, and reference herein to one of suchisomeric forms is meant to refer to at least one of such isomeric forms.One of ordinary skill in the art will recognize that compounds accordingto this invention may exist, for example, in a single isomeric formwhereas other compounds may exist in the form of a regioisomericmixture.

Whether stated explicitly or not in any part of the written descriptionand claims, it is understood that each substituent and member assignmentin the context of this invention is made independently of any othermember and substituent assignment, unless stated otherwise. By way of afirst example on substituent terminology, if substituent S¹ _(example)is one of S₁ and S₂, and substituent S² _(example) is one of S₃ and S₄,then these assignments refer to embodiments of this invention givenaccording to the choices S¹ _(example) is S₁ and S² _(example) is S₃; S¹_(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ and S²_(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent R assignments described herein. The foregoing conventiongiven herein for substituents extends, when applicable, to members suchas X, Y, Z, and W, and the index n.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments and equivalentsthereof. By way of a second example on substituent terminology, if it isherein described that substituent S_(example) is one of S₁, S₂, and S₃,this listing refers to embodiments of this invention for whichS_(example) is S₁; S_(example) is S₂; S_(example) is S₃; S_(example) isone of S₁ and S₂; S_(example) is one of S₁ and S₃; S_(example) is one ofS₂ and S₃; S_(example) is one of S₁, S₂ and S₃; and S_(example) is anyequivalent of each one of these choices. The shorter terminology“S_(example) is one of S₁, S₂, and S₃” is accordingly used herein forthe sake of brevity, but not by way of limitation. The foregoing secondexample on substituent terminology, which is stated in generic terms, ismeant to illustrate the various substituent R assignments describedherein. The foregoing convention given herein for substituents extends,when applicable, to members such as X, Y, Z, and W, and the index n.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is realized. By way of example, the term C₁₋₃ refersindependently to embodiments that have one carbon member (C₁),embodiments that have two carbon members (C₂), and embodiments that havethree carbon members (C₃).

When any variable referring to a substituent, compound member or index,occurs more than once, the full range of assignments is meant to applyto each occurrence, independently of the specific assignment(s) to anyother occurrence of such variable.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

The invention also features a pharmaceutical composition for treating orpreventing an H₄ receptor-mediated condition in a subject, comprising atherapeutically effective amount of at least one H₄ receptor modulatorselected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates thereof, pharmaceutically acceptable salts,amides and esters thereof. In addition, the invention features apharmaceutical composition for inhibiting leukocyte recruitment in asubject, comprising a therapeutically effective amount of at least oneleukocyte recruitment inhibitor selected from compounds of formulae (I)and (II), enantiomers, diastereomers, racemates thereof,pharmaceutically acceptable salts, amides and esters thereof. Theinvention additionally features an anti-inflammatory composition,comprising a therapeutically effective amount of at least oneanti-inflammatory compound selected from compounds of formulae (I) and(II), enantiomers, diastereomers, racemates thereof, pharmaceuticallyacceptable salts, amides and esters thereof.

The invention features methods for treating or preventing inflammationin a subject, comprising administering to the subject in connection withan inflammatory response a pharmaceutical composition that comprises atherapeutically effective amount of at least one anti-inflammatorycompound selected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates thereof, pharmaceutically acceptable salts,amides and esters thereof. The invention also features methods fortreating or preventing an H₄ receptor-mediated condition in a subject,comprising administering to the subject a pharmaceutical compositionthat comprises a therapeutically effective amount of at least one H₄receptor modulator selected from compounds of formulae (I) and (II),enantiomers, diastereomers, racemates thereof, pharmaceuticallyacceptable salts, amides and esters thereof. In addition, the inventionfeatures methods for modulating an H₄ receptor, comprising exposing anH₄ receptor to at least one compound selected from compounds of formulae(I) and (II), enantiomers, diastereomers, racemates thereof,pharmaceutically acceptable salts, amides and esters thereof.Furthermore, the invention features methods for inhibiting leukocyterecruitment in a subject, comprising administering to the subject apharmaceutical composition that comprises a therapeutically effectiveamount of at least one leukocyte recruitment inhibitor selected fromcompounds of formulae (I) and (II), enantiomers, diastereomers,racemates thereof, pharmaceutically acceptable salts, amides and estersthereof.

DETAILED DESCRIPTION

The present invention is directed to compounds of formula (I) or (II),enantiomers, diastereomers, racemates thereof, pharmaceuticallyacceptable salts, amides and esters thereof, as herein defined,pharmaceutical compositions that contain at least one of such compounds,methods of using, including treatment and/or prevention of conditionssuch as those that are mediated by the H₄ receptor, and methods ofmaking such pharmaceutical compositions.

The following terms are defined below, and by their usage throughout thedisclosure.

“Alkyl” includes straight chain and branched hydrocarbons with at leastone hydrogen removed to form a radical group. Alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, andso on. Alkyl does not include cycloalkyl.

“Alkenyl” includes straight chain and branched hydrocarbon radicals asabove with at least one carbon-carbon double bond (sp²). Unlessindicated otherwise by the prefix that indicates the number of carbonmembers, alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl(or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl,butadienyls, pentenyls, hexa-2,4-dienyl, and so on.

“Alkynyl” includes straight chain and branched hydrocarbon radicals asabove with at least one carbon-carbon triple bond (sp). Unless indicatedotherwise by the prefix that indicates the number of carbon members,alkynyls include ethynyl, propynyls, butynyls, and pentynyls.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein.

“Alkoxy” includes a straight chain or branched alkyl group with aterminal oxygen linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and so on. “Aminoalkyl”, “thioalkyl”, and “sulfonylalkyl” areanalogous to alkoxy, replacing the terminal oxygen atom of alkoxy with,respectively, NH (or NR), S, and SO₂.

Unless indicated otherwise by the prefix that indicates the number ofcarbon members, “cycloalkyl” includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and so on.

Unless indicated otherwise by the prefix that indicates the number ofmembers in the cyclic structure, “heterocyclyl”, “heterocyclic” or“heterocycle” is a 3- to 8-member aromatic, saturated, or partiallysaturated single or fused ring system that comprises carbon atomswherein the heteroatoms are selected from N, O, and S. Examples ofheterocyclyls include thiazoylyl, furyl, pyranyl, isobenzofuranyl,pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl,indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl,piperazinyl, indolinyl, and morpholinyl. For example, preferredheterocyclyls or heterocyclic radicals include morpholinyl, piperazinyl,pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino, and morepreferably, piperidyl.

Carbocycle is a cycloalkyl or a partially saturated cycloalkyl that isnot benzo

“Aryl” includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, and soon, any of which may be optionally substituted. Aryl also includesarylalkyl groups such as benzyl, phenethyl, and phenylpropyl. Arylincludes a ring system containing an optionally substituted 6-memberedcarbocyclic aromatic ring, said system may be bicyclic, bridged, and/orfused. The system may include rings that are aromatic, or partially orcompletely saturated. Examples of ring systems include indenyl,pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl,benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on.Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl,imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzothiazolyl.

“Halo” includes fluoro, chloro, bromo, and iodo, and is preferablyfluoro or chloro.

As in standard chemical nomenclature, the group phenyl is hereinreferred to as “phenyl” or as “Ph”.

“Patient” or “subject” includes mammals such as human beings and animals(e.g., dogs, cats, horses, rats, rabbits, mice, non-human primates) inneed of observation, experiment, treatment or prevention in connectionwith the relevant disease or condition. Preferably, the patient is ahuman being.

“Composition” includes a product comprising the specified ingredients inthe specified amounts, including in the effective amounts, as well asany product that results directly or indirectly from combinations of thespecified ingredients in the specified amounts.

“Therapeutically effective amount” or “effective amount” andgrammatically related terms mean that amount of active compound orpharmaceutical agent that elicits the biological or medicinal responsein a tissue system, animal or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician, whichincludes alleviation of the symptoms of the disease or disorder beingtreated.

Table of Acronyms Term Acronym Tetrahydrofuran THF N,N-DimethylformamideDMF N,N-Dimethylacetamide DMA Dimethyl sulfoxide DMSOtert-Butylcarbamoyl BOC Bovine serum albumin BSA High-pressure liquidchromatography HPLC Thin layer chromatography TLC

Particular preferred compounds of the invention comprise abenzoimidazole compound of formula (I) or (II), or an enantiomer,diastereomer, racemate thereof, or a pharmaceutically acceptable salt,amide or ester thereof, wherein R¹⁻¹⁴, X, Y, Z, W, and n have any of themeanings defined hereinabove and equivalents thereof, or at least one ofthe following assignments and equivalents thereof. Such assignments maybe used where appropriate with any of the definitions, claims orembodiments defined herein:

Preferably, W is N or CR⁷.

Preferably, X is N or CH.

Preferably, Y is CR¹²R¹³.

More preferably, Y is CH₂.

Preferably, Z is N or CH.

Preferably, n=1 or 2.

More preferably, n=1.

Preferably, R¹ is selected from the group consisting of H, methyl,ethyl, isopropyl, cyclopropyl, F, Cl, Br, cyano, phenyl, carboxymethyl,dimethylcarboxamido, or CH₂OMe.

More preferably, R¹ is H, methyl, F, or Cl.

Preferably, R² is independently selected from the group consisting of H,methyl, ethyl, isopropyl, t-butyl, cyclopropyl, CF₃, OCF₃, F, Cl, Br,cyano, phenyl, carboxymethyl, dimethylcarboxamido, or benzoyl.

More preferably, R² is H, F, Cl, methyl, CF₃, OCF₃, or t-butyl.

Preferably, R³ is independently selected from the group consisting of H,methyl, ethyl, isopropyl, t-butyl, cyclopropyl, CF₃, OCF₃, F, Cl, Br,cyano, phenyl, carboxymethyl, dimethylcarboxamido, or benzoyl.

More preferably, R³ is H, F, Cl, methyl, CF₃, OCF₃, or t-butyl.

Preferably, R⁴ is selected from the group consisting of H, methyl,ethyl, isopropyl, cyclopropyl, R, Cl, Br, cyano, phenyl, carboxymethyl,dimethylcarboxamido, or CH₂OMe.

More preferably, R⁴ is H, methyl, F, or Cl.

Most preferably, one or two of R¹⁻⁴ are not H.

Preferably, R⁵ is H, F, Cl, methyl, or ethyl.

More preferably, R⁵ is F, Cl, methyl, hydroxymethyl, hydroxyethyl,pyrrolidinylmethyl, or diethylaminomethyl.

More preferably, R⁶ is H, F, Cl, or methyl.

More preferably, R⁷ is H, F, Cl, or methyl.

Most preferably, R⁵ is Cl, methyl, or hydroxymethyl.

Preferably, R⁸ is H, methyl, or OH.

More preferably, R⁸ is H.

Preferably, R⁹ and R¹⁰ are, independently, selected from the groupconsisting of

a) H,

b) methyl, ethyl, propyl, isopropyl, and

c) trifluoromethyl.

Most preferably, R⁹ and R¹⁰ are, independently, H or methyl.

Preferably, R¹¹ is H, methyl, or ethyl.

More preferably, R¹¹ is methyl.

Compounds of formula (I) or (II) also comprise compounds that satisfyany one of the combinations of definitions given herein and equivalentsthereof.

It is understood that some compounds referred to herein are chiraland/or have geometric isomeric centers, for example E- and Z-isomers.The present invention encompasses all such optical, includingstereoisomers and racemic mixtures, diastereomers, and geometric isomersthat possess the activity that characterizes the compounds of thisinvention. In addition, certain compounds referred to herein can existin solvated as well as unsolvated forms. It is understood that thisinvention encompasses all such solvated and unsolvated forms thatpossess the activity that characterizes the compounds of this invention.Compounds according to the present invention that have been modified tobe detectable by some analytic technique are also within the scope ofthis invention. An example of such compounds is an isotopically labeledcompound, such as an ¹⁸F isotopically labeled compound that may be usedas a probe in detection and/or imaging techniques, such as positronemission tomography (PET) and single-photon emission computed tomography(SPECT). Another example of such compounds is an isotopically labeledcompound, such as a deuterium and/or tritium labeled compound that maybe used in reaction kinetic studies.

It is understood that substitutions and combinations of substitutionsrecited herein, whether stated explicitly or not, refer to substitutionsthat are consistent with the valency of the member being substituted.For example, a substitution applied to a carbon member refers to thetetravalency of C; it refers to the trivalency of N when applied to anitrogen member; and it refers to the tetravalency of a nitrogen memberthat is conventionally characterized with a positive electric charge.Valence allowed options are part of the ordinary skill in the art.

The “pharmaceutically acceptable salts, amides and/or esters thereof”refer to those salts, amides and ester forms of the compounds of thepresent invention that would be apparent to the pharmaceutical chemist,i.e., those that are non-toxic and that would favorably affect thepharmacological properties of said compounds of the present invention.Those compounds having favorable pharmacological properties would beapparent to the pharmaceutical chemist, i.e., those that are non-toxicand that possess such pharmacological properties to provide sufficientpalatability, absorption, distribution, metabolism and excretion. Otherfactors, more practical in nature, that are also important in theselection are cost of raw materials, ease of crystallization, yield,stability, hygroscopicity, and flowability of the resulting bulk drug.

Representative acids and bases that may be used in the preparation ofpharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichlorolactic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucuronic acid, L-glutamic acid, x-oxo-glutaric acid, glycolicacid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

See, for example, S. M. Berge, et al., “Pharmaceutical Salts”, J. Pharm.Sci. 1977, 66:1-19, which is incorporated herein by reference. Examplesof suitable esters include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl,substituted phenyl, and phenylC₁₋₆alkyl-esters. Preferred esters includemethyl esters.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound that may not be specificallydisclosed, but that converts to the specified compound in vivo afteradministration to the patient. Analogously, the term “compound”, whenapplied to compounds within the scope of this invention, shall encompassin addition to a specific compound of formula (I) or (II), a compound(or prodrug) that converts to the specifically disclosed compound invivo after administration, even if such prodrug is not explicitlydisclosed herein. Conventional procedures for the selection andpreparation of suitable prodrug derivatives are described, for example,in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Compounds where W is CR⁷ were made according to the synthetic methodsoutlined in Schemes 1 and 2 and examples of such compounds are providedin the group:

EX Compound

-   1    2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,5-dimethyl-1H-benzoimidazole;-   2    2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;-   3    2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethoxy-1H-benzoimidazole;-   4    5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   6    4,5-Dimethyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   7    5-tert-Butyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimidazole;-   8    5-tert-Butyl-2-{3-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-phenyl}-1H-benzoimidazole;-   9    (1-{3-[4-(5-tert-Butyl-1H-benzoimidazol-2-yl)-2-chloro-phenoxy]-propyl}-pyrrolidin-3-yl)-dimethylamine;-   10    5-Chloro-2-{3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-6-methyl-1H-benzoimidazole;-   11    2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;-   12    5-Methyl-2-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-naphthalen-1-yl}-1H-benzoimidazole;-   13    4-[3-(5-tert-Butyl-1H-benzoimidazol-2-yl)-phenoxy]-1-(4-methyl-piperazin-1-yl)-butan-1-one;-   14    5-Chloro-2-[3-chloro-4-(3-piperazin-1-yl-propoxy)-phenyl]-6-fluoro-1H-benzoimidazole;-   15    5-tert-Butyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   16    2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,6-dimethyl-1H-benzoimidazole;-   17    2-{2-Chloro-4-[2-methyl-3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;-   18    5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-methyl-1H-benzoimidazole;-   19    6-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;-   20    5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   21    5-Chloro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   22    2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,6-dimethyl-1H-benzoimidazole;-   23    5-Chloro-6-methyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimidazole;-   24    5-Chloro-6-fluoro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   25    2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-benzoimidazole;-   26    5,6-Difluoro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   27    2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   28    2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,5-dimethyl-1H-benzoimidazole;-   29    5,6-Dimethyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimidazole;-   30    2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,6-dimethyl-1H-benzoimidazole;-   31    2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;-   32    5-tert-Butyl-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   33    2-{3-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethyl-1H-benzoimidazole;-   34    5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-fluoro-1H-benzoimidazole;-   35    5,6-Dichloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   36    5-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   37    5-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-fluoro-1H-benzoimidazole;-   38    5-Chloro-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   39    2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-benzoimidazole;-   40    5,6-Dichloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   41    5-Chloro-6-methyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   42    2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-benzoimidazole;-   43    5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   44    2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethyl-1H-benzoimidazole;-   45    5-Chloro-6-fluoro-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   46    5-Methyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   47    2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   48    2-{3-Methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   49    2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   50    5-Chloro-6-fluoro-2-{3-methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   51    2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methoxy-1H-benzoimidazole;-   52    5-tert-Butyl-2-{3,5-dibromo-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   53    2-{2-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethyl-1H-benzoimidazole;-   54    2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethyl-1H-benzoimidazole;-   55    2-{3-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   56    (2-{3-[4-(4-Methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimidazol-5-yl)-phenyl-methanone;-   57    6-Chloro-2-{2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;-   58    5-tert-Butyl-2-{3-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   59    2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,5-dimethyl-1H-benzoimidazole;-   60    5-Chloro-6-methyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   61    5-Chloro-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   62    5-Chloro-6-fluoro-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   63    5-tert-Butyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   64    5-Methyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   65    2-{4-[3-(1-Methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   66    6-Chloro-2-{2-fluoro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;-   67    5-Fluoro-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   68    4-Chloro-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   69    6-Chloro-4-methyl-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   70    5-Chloro-2-{2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-6-fluoro-1H-benzoimidazole;-   71    2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-3H-naphtho[1,2-d]imidazole;-   72    4,6-Dimethyl-2-{2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   73    2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;-   74    2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-fluoro-4-methyl-1H-benzoimidazole;-   75    2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-3H-naphtho[1,2-d]imidazole;-   76    6-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazole;-   77    6-Chloro-2-{2-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;-   78    2-{3-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;-   79    4,6-Dimethyl-2-{3-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-phenyl}-1H-benzoimidazole;-   80    5-Chloro-2-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   81    2-{4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   82    {2-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethyl-amine;-   83    {2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethyl-amine;-   84    4-{3-[4-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-[1,4]diazepan-5-one;-   85    4-{3-[4-(5-tert-Butyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-1-methyl-[1,4]diazepan-5-one;-   86    5-tert-Butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   87    5-tert-Butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   88    6-Chloro-4-methyl-2-[2-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-1H-benzoimidazole;-   89    5-Fluoro-4-methyl-2-[2-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-1H-benzoimidazole;-   90    6-Chloro-2-{4-[3-(1-ethyl-piperidin-4-yl)-propoxy]-2-methyl-phenyl}-4-methyl-1H-benzoimidazole;-   91    {2-[3-Chloro-4-(4-methyl-1H-benzoimidazol-2-yl)-phenoxy]-ethyl}-methyl-(1-methyl-piperidin-4-yl)-amine;-   92    6-Chloro-4-methyl-2-{2-methyl-4-[2-(1-methyl-piperidin-4-yloxy)-ethoxy]-phenyl}-1H-benzoimidazole;-   93    6-Chloro-4-methyl-2-{2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   94    5-Fluoro-4-methyl-2-{2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;-   95    6-Fluoro-7-methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;-   96    7-Methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;-   97    6,7-Dimethyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;-   98    5-Chloro-7-methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;-   99    5,7-Dimethyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;-   100    5-Chloro-7-methyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;-   101    6-Fluoro-7-methyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;-   102    6-Fluoro-7-methyl-2-{3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-phenyl}-1H-benzoimidazole;    and-   176    {2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-methanol.

Compounds where W is N were made according to the synthetic methodsoutlined in Schemes 1 through 6 and examples of such compounds areprovided in the group:

EX Compound

-   103    6-Chloro-4-methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   104    4-Methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   105    5-Fluoro-4-methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   106    4-Methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   107    4,5-Dimethyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   108    4-Chloro-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   109    6-Chloro-4-methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   110    4-Methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   111    5-Fluoro-4-methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   112    4,5-Dimethyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   113    4,6-Dimethyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   114    4-Chloro-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   115    2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-5-fluoro-4-methyl-1H-benzoimidazole;-   116    2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methyl-1H-benzoimidazole;-   117    6-Chloro-2-{4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methyl-1H-benzoimidazole;-   118    2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4,6-dimethyl-1H-benzoimidazole;-   119    2-{4-Methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methyl-1H-benzoimidazole;-   120    5-Fluoro-2-{4-methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methyl-1H-benzoimidazole;-   121    5-Fluoro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   122    4-Methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   123    6-Chloro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   124    4,5-Dimethyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   125    4,6-Dimethyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   126    5-Chloro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;-   127    5-Fluoro-4-methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-4-pyrrolidin-1-ylmethyl-pyridin-3-yl}-1H-benzoimidazole;-   128    2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole;-   129    2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole;-   130    2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-6-chloro-4-methyl-1H-benzoimidazole;-   131    2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimethyl-1H-benzoimidazole;-   132    2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole;-   133    2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro-4-methyl-1H-benzoimidazole;-   134    2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-tert-butyl-1H-benzoimidazole;-   135    5-tert-Butyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   136    2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole;-   137    2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole;-   138    4,6-Dimethyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   139    4-Methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   140    4,5-Dimethyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   141    5-Fluoro-4-methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   142    6-Chloro-4-methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   143    5-Fluoro-4-methyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   144    4,5-Dimethyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   145    4,6-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   146    4-Methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   147    5-Fluoro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   148    4-Chloro-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   149    4,5-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   150    6-Chloro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   151    5-Chloro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   152    5-tert-Butyl-2-[2-(4-piperidin-4-yl-butoxy)-pyridin-4-yl]-1H-benzoimidazole;-   153    4,6-Dimethyl-2-[2-(4-piperidin-4-yl-butoxy)-pyridin-4-yl]-1H-benzoimidazole;-   154    2-{2-[4-(1-Ethyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole;-   155    4,6-Dimethyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   156    4-Methyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   157    6-Chloro-4-methyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   158    2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole;-   159    2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole;-   160    4-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   161    2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole;-   162    2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimethyl-1H-benzoimidazole;-   163    6-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole;-   164    5-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole;-   165    5-Fluoro-4-methyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   166    5-Chloro-6-fluoro-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   167    5-tert-Butyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   168    4,5-Dimethyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   169    2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimethyl-1H-benzoimidazole;-   170    5-Chloro-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   171    5-Chloro-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-6-fluoro-1H-benzoimidazole;-   172    5-tert-Butyl-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;-   173    2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-chloro-1H-benzoimidazole;-   174    2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro-6-fluoro-1H-benzoimidazole;-   175    2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro-1H-benzoimidazole;    and-   177    {4-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-6-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-3-yl}-methanol.

Embodiments of pharmaceutical compositions and methods of use ofcompounds according to this invention are provided by pharmaceuticalcompositions that comprise, and by methods of use of, any of thecompounds described herein and combinations thereof.

Embodiments of pharmaceutical compositions for treating or preventing anH₄ receptor-mediated condition in a subject that comprise atherapeutically effective amount of at least one H₄ receptor modulatorselected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates thereof, pharmaceutically acceptable salts,amides and esters thereof, further comprise a pharmaceuticallyacceptable carrier.

Embodiments of pharmaceutical compositions for inhibiting leukocyterecruitment in a subject that comprise a therapeutically effectiveamount of at least one leukocyte recruitment inhibitor selected fromcompounds of formulae (I) and (II), enantiomers, diastereomers,racemates thereof, pharmaceutically acceptable salts, amides and estersthereof, further comprise a pharmaceutically acceptable carrier.

Embodiments of anti-inflammatory compositions that comprise atherapeutically effective amount of at least one anti-inflammatorycompound selected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates thereof, pharmaceutically acceptable salts,amides and esters thereof, further comprise a pharmaceuticallyacceptable carrier.

Embodiments of methods for treating or preventing inflammation in asubject that comprise administering to the subject in connection with aninflammatory response a pharmaceutical composition comprising atherapeutically effective amount of at least one anti-inflammatorycompound selected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates thereof, pharmaceutically acceptable salts,amides and esters thereof, include methods wherein said inflammatoryresponse is a response to at least one of the conditions: inflammatorydisorders, allergic disorders, dermatological disorders, autoimmunedisease, lymphatic disorders, itchy skin, and immunodeficiencydisorders.

Embodiments of methods for treating or preventing inflammation in asubject that comprise administering to the subject in connection with aninflammatory response a pharmaceutical composition comprising atherapeutically effective amount of at least one anti-inflammatorycompound selected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates thereof, pharmaceutically acceptable salts,amides and esters thereof, include methods wherein said inflammatoryresponse is a response to chemotherapy.

Embodiments of methods for treating or preventing inflammation in asubject that comprise administering to the subject in connection with aninflammatory response a pharmaceutical composition comprising atherapeutically effective amount of at least one anti-inflammatorycompound selected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates thereof, pharmaceutically acceptable salts,amides and esters thereof, include methods wherein at least one of thefollowing is satisfied: said inflammatory response is a response to aphysical stimulus; said inflammatory response is a response to achemical stimulus; said inflammatory response is a response toinfection; said inflammatory response is a response to an invasion by abody that is foreign to said subject; said inflammatory response is aresponse to an immunological stimulus; said inflammatory response is aresponse to a non-immunological stimulus; said inflammatory response isa response to at least one of the conditions: allergy, asthma, chronicobstructed pulmonary disease (COPD), atherosclerosis, rheumatoidarthritis, multiple sclerosis, inflammatory bowel disease, and morespecifically wherein said inflammatory bowel disease is at least one ofCrohn's disease and ulcerative colitis, psoriasis, allergic rhinitis,scleroderma, autoimmune thyroid disease, immune-mediated diabetesmellitus, and lupus; said inflammatory response is a response to atleast one of the conditions: myasthenia gravis, autoimmune neuropathy,and more specifically wherein said autoimmune neuropathy isGuillain-Barré neuropathy, autoimmune uveitis, autoimmune hemolyticanemia, pernicious anemia, autoimmune thrombocytopenia, temporalarteritis, anti-phospholipid syndrome, vasculitides, and morespecifically wherein said vasculitides is Wegener's granulomatosis,Behcet's disease, dermatitis herpetiformis, pemphigus vulgaris,vitiligio, primary biliary cirrhosis, autoimmune hepatitis, autoimmuneoophoritis, autoimmune orchitis, autoimmune disease of the adrenalgland, polymyositis, dermatomyositis, spondyloarthropathy, and morespecifically wherein said spondyloarthropathy is ankylosing spondylitis,and Sjogren's syndrome; said inflammatory response is acuteinflammation; said inflammatory response is allergic inflammation; andsaid inflammatory response is chronic inflammation. Administration inconnection with an inflammatory response according to the presentinvention includes administration at a time that is at least one ofprior to, at the onset of, and after inflammation is detected.

Embodiments of methods for modulating an H₄ receptor that compriseexposing an H₄ receptor to at least one compound selected from compoundsof formulae (I) and (II), enantiomers, diastereomers, racemates thereof,pharmaceutically acceptable salts, amides and esters thereof, includemethods wherein at least one of the following is satisfied: said atleast one compound modulates the H₄ receptor as a receptor antagonist,and said at least one compound of modulates the H₄ receptor as areceptor partial agonist.

If more than one active agent is administered, such as a compound offormula (I) or (II), the therapeutically effective amount may be ajointly effective amount.

An illustration of the invention is a pharmaceutical composition made bymixing at least one benzoimidazole compound selected from compounds offormulae (I) and (II), enantiomers, diastereomers, racemates thereof,pharmaceutically acceptable salts, amides and esters thereof, and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing atleast one benzoimidazole compound selected from compounds of formulae(I) and (II), enantiomers, diastereomers, racemates thereof,pharmaceutically acceptable salts, amides and esters thereof, and apharmaceutically acceptable carrier.

Another example of the invention is the use of a composition thatcomprises at least one benzoimidazole compound selected from compoundsof formulae (I) and (II), enantiomers, diastereomers, racemates thereof,pharmaceutically acceptable salts, amides and esters thereof, in thepreparation of a medication for treating any one of the conditionsreferred to herein; one of such conditions is inflammation. Anotherexample of the invention is the use of a composition that comprises atleast one benzoimidazole compound selected from compounds of formulae(I) and (II), enantiomers, diastereomers, racemates thereof,pharmaceutically acceptable salts, amides and esters thereof, in thetreatment or prevention of any one of the conditions referred to herein;one of such conditions is inflammation.

Compounds according to the present invention may be made according toprocesses within the skill of the art and/or according to processes ofthis invention, such as those described in the schemes and examples thatfollow and by matrix or combinatorial methods. To obtain the variouscompounds herein, starting materials may be employed that carry theultimately desired substituents though the reaction scheme with orwithout protection as appropriate. Starting materials may be obtainedfrom commercial sources or synthesized by methods known to one skilledin the art. Alternatively, it may be necessary to employ, in the placeof the ultimately desired substituent, a suitable group, which may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Any product containing a chiral center may beseparated into its enantiomers by conventional techniques. Those ofordinary skill in the art will be able to modify and adapt the guidanceprovided herein to make compounds according to the present invention.

Embodiments of processes illustrated herein include, when chemicallymeaningful, one or more steps such as hydrolysis, halogenation,protection, and deprotection. These steps can be implemented in light ofthe teachings provided herein and the ordinary skill in the art.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. Inaddition, compounds of the invention may be modified by using protectinggroups; such compounds, precursors, or prodrugs are also within thescope of the invention. This may be achieved by means of conventionalprotecting groups, such as those described in “Protective Groups inOrganic Chemistry”, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 3^(rd)ed., John Wiley & Sons, 1999. The protecting groups may be removed at aconvenient subsequent stage using methods known from the art.

Referring to Schemes 1 and 2, there are disclosed the following notesand additions. The starting materials for the steps described belowregarding Schemes 1 and 2 are commercially available or easilyaccessible to those skilled in the art.

Compounds of formula (I) or (II) are prepared by condensing a suitablysubstituted diamino benzene (III) under oxidizing conditions with asuitably substituted benzaldehyde (IV′) or (IV″) to form a compound offormula (I) when the benzaldehyde (IV′) has a para ether substitutionwith respect to the aldehyde group (Scheme 1), or a compound of formula(II) when the benzaldehyde (IV″) has a meta ether substitution withrespect to the aldehyde group (Scheme 2). Suitable oxidants for thisstep include air, Na₂S₂O₅, Oxone, and chemically compatible oxidantsthat have a similar oxidizing power, and mixtures thereof.

This condensation is preferably performed in a heated medium in achemically compatible solvent. Reaction medium temperatures rangepreferably from about 40° C. to about 150° C., more preferably about 80°C. to about 100° C. Solvents that can be used for this reaction includedioxane, THF, benzotrifluoride, toluene, 1,2-dichloroethane, DMA, andDMSO, preferably DMF, and mixtures thereof.

Suitably substituted benzaldehydes (IV′) and (IV″) can be preparedaccording to procedures known in the art. In one preparation procedure,a suitably substituted hydroxy benzaldehyde is reacted with a suitablysubstituted moiety to form the ether link in compounds (IV′) and (IV″).Reaction with suitably substituted 4-hydroxy benzaldehyde leads to theformation of compound (IV′), and reaction with a suitably substituted3-hydroxy benzaldehyde leads to the formation of compound (IV″).

Regarding the following Schemes 3 through 6, the starting materials forthe steps described below are commercially available or easilyaccessible to those skilled in the art.

Particular aldehydes (IV′) may prepared as shown in Scheme 3. A suitableprimary alcohol (V) is treated with a base such as sodium hydride,potassium hydride, potassium t-butoxide, or lithium diisopropylamide(LDA), in a polar solvent such as DMF or THF. Preferred conditionsinclude sodium hydride in DMF. The resulting alkoxide is then treatedwith an optionally substituted 6-chloronicotinonitrile to form an arylether of formula (VII). The reaction may be performed without heating orwith heating up to about 60° C. Where R⁵ is H, compounds of formula(VII) may be further reacted to install a non-hydrogen substituent atthat position. Compounds of formula (VII) are treated with a strong basesuch as LDA, lithium 2,2,6,6-tetramethylpiperidine (LTMP), or lithiumbis(trimethylsilyl)amide (LHMDS), at low temperatures of between about−78° C. and about −50° C., in a solvent such as THF, diethyl ether, ortoluene. Preferred conditions include the use of LDA or LTMP in THF. Theresulting lithiated species is treated with a suitable electrophile, attemperatures between about −78° C. and room temperature. Preferredelectrophiles are methyl iodide and hexachloroethane. When R⁵ is thenchloride, additional substituents may be introduced at that positionusing nucleophilic substitution. Suitable nucleophiles includeC₁₋₃alkoxides and primary and secondary amines. In a particularembodiment, the preferred nucleophile is methoxide. Once the desiredsubstituents are in place, the nitrile functionality in compounds offormula (VII) is then reduced with a suitable reducing agent, such asdiisobutylaluminum hydride, in a solvent such as toluene or THF, to formaldehydes of formula (IV′) where W is N.

Referring to Scheme 4, a suitable primary alcohol of formula (VIII) isreacted with an appropriately substituted 2-chloropyridine of formula(IX) to generate pyridyl ethers of formula (X), as shown in Scheme 3.Preferred reaction conditions employ sodium hydride in DMF. Where R⁵ ishydrogen, additional substituents may be introduced at that position byreaction of ethers of formula (X) with a strong, hindered base followedby a suitable electrophile as described in Scheme 3. Preferredelectrophiles include methyl iodide and hexachloroethane. Once thedesired substituents are in place, nitrites of formula (X) may bereduced to aldehydes of formula (IV″), where W is N as shown, throughreduction of the nitrile group as described in Scheme 3. Preferredreducing agents include diisobutylaluminum hydride.

Referring to Scheme 5, dihalopyridines of formula (XI), where Hal iseither Cl or Br, are reacted with primary alcohols of formulae (V) or(VIII), using conditions described above, to form pyrido ethers offormula (XII). The resulting 3-halopyridines can then be converted tothe corresponding 3-formylpyridines of formula (XIII) by halogen-metalexchange with a suitable alkyllithium reagent, in a suitable solventsuch as THF or diethyl ether, followed by quenching with a formylequivalent, such as DMF, N-formylpiperidine, or ethyl chloroformate.Preferred conditions employ n-BuLi or t-BuLi in THF, and a preferredelectrophile is DMF. Alternatively, 3-halopyridines of formula (XII) maybe converted into aldehydes of formula (XIV) according to the directedlithiation and formyl trapping procedures described in Schemes 3 and 4.Aldehydes of formula (XIV), where Hal is Br, may be further processedthrough a three-step sequence to provide aldehydes of formula (XV). Tothat end, the aldehyde is first protected as a suitable group, such asan acetal. The bromide may then reacted via halogen-metal exchange usingan alkyllithium reagent and electrophilic trapping, as described abovein the current scheme, to introduce substituents E. Preferredelectrophilic reagents include methyl iodide and hexachloroethane, toproduce compounds of formula (XV) where E is methyl or chloro,respectively. Aldehydes of formulae (XIII), (XIV), and (XV) may then beprocessed into compound of the invention as shown in Schemes 1 and 2above.

Referring to Scheme 6, aldehydes of formula (XIV) may be converted toaminomethyl analogs of formula (XVI) via reductive amination, using asuitable reducing agent such as NaCNBH₃ or Na(OAc₃)BH, in a suitablesolvent such as 1,2-dichloroethane or methanol. Optional additives mayinclude acetic acid or a Lewis acid such as ZnCl₂. Amines of formula(XVI) may then be transformed into aldehydes of formula (XVII) byperforming halogen-metal exchange and quenching procedures as describedabove. Aldehydes of formula (XVII) may be processed into compounds ofthe invention according to Scheme 1.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as resolution, for exampleby formation of diastereomeric salts, kinetic resolution includingvariants thereof, such as dynamic resolution, preferentialcrystallization, biotransformation, enzymatic transformation, andpreparative chromatography. The compounds may be prepared in racemicform, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The compounds may, forexample, be resolved into their component enantiomers by standardtechniques, such as the formation of diastereomeric pairs by saltformation with an optically active acid, such as(−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acidfollowed by fractional crystallization and regeneration of the freebase. The compounds may also be resolved by formation of diastereomericesters or amides, followed by chromatographic separation and removal ofthe chiral auxiliary. Alternatively, the compounds may be separatedusing a chiral HPLC column.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

The expression of the H₄ receptor in immune cells, including someleukocytes and mast cells, establishes it as an important target fortherapeutic intervention in a range of immunological and inflammatorydisorders (such as allergic, chronic, or acute inflammation).Specifically H₄ receptor ligands are expected to be useful for thetreatment or prevention of various mammalian disease states.

Thus, according to the invention, the disclosed compounds, whetherpartial agonists or antagonists of the H₄ receptor, and compositions areuseful for the amelioration of symptoms associated with, the treatmentof, and the prevention of, the following conditions and diseases:inflammatory disorders, allergic disorders, dermatological disorders,autoimmune disease, lymphatic disorders, and immunodeficiency disorders,including the more specific conditions and diseases given above. Thedisclosed compounds may also be useful as adjuvants in chemotherapy orin the treatment of itchy skin.

Aspects of the invention include (a) a pharmaceutical compositioncomprising a benzoimidazole compound selected from compounds of formulae(I) and (II), enantiomers, diastereomers, racemates thereof,pharmaceutically acceptable salts, amides and esters thereof, and apreferred compound as described herein, and a pharmaceuticallyacceptable carrier; (b) a packaged drug comprising (1) a pharmaceuticalcomposition comprising at least one benzoimidazole compound selectedfrom compounds of formulae (I) and (II), enantiomers, diastereomers,racemates thereof, pharmaceutically acceptable salts, amides and estersthereof, or one or more preferred compounds as described herein, and apharmaceutically acceptable carrier, and (2) instructions for theadministration of said composition for the treatment or prevention of anH₄-mediated disease or condition.

Embodiments of this invention provide methods for treating anH₄-mediated condition in a patient, said methods comprisingadministering to the patient a pharmaceutically effective amount of acomposition comprising at least one benzoimidazole compound selectedfrom compounds of formulae (I) and (II), enantiomers, diastereomers,racemates thereof, pharmaceutically acceptable salts, amides and estersthereof, and other disclosed or preferred compounds. In theseconditions, the action of the H₄ receptor is involved. For example, theinvention features a method for treating an H₄ mediated condition in apatient, said method comprising administering to the patient apharmaceutically effective H₄-antagonizing amount of a compositioncomprising at least one benzoimidazole compound selected from compoundsof formulae (I) and (II), enantiomers, diastereomers, racemates thereof,pharmaceutically acceptable salts, amides and esters thereof. As usedherein, “treating” a disorder, and grammatically related terms, meaneliminating or otherwise ameliorating the cause and/or effects thereof.Terms such as to “inhibit”, and grammatically related terms, the onsetof a disorder or event, and to “prevent” a disorder or condition, andgrammatically related terms, mean preventing, delaying or reducing thelikelihood of such onset.

The effect of an antagonist may also be produced by an inverse agonist.Inverse agonism describes the property of a compound to actively turnoff a receptor that displays constitutive activity. Constitutiveactivity can be identified in cells that have been forced toover-express the human H₄ receptor. Constitutive activity can bemeasured by examining cAMP levels or by measuring a reporter genesensitive to cAMP levels after a treatment with a cAMP-stimulating agentsuch as forskolin. Cells that over-express H₄ receptors will displaylower cAMP levels after forskolin treatment than non-expressing cells.Compounds that behave as H₄ agonists will dose-dependently lowerforskolin-stimulated cAMP levels in H₄-expressing cells. Compounds thatbehave as H₄ inverse agonists will dose-dependently stimulate cAMPlevels in H₄-expressing cells. Compounds that behave as H₄ antagonistswill block either H₄ agonist-induced inhibition of cAMP or H₄ inverseagonist-induced increases in cAMP.

Further embodiments of the invention include disclosed compounds thatare inhibitors of a mammalian histamine H₄ receptor function, inhibitorsof inflammation or inflammatory responses in vivo or in vitro,modulators of the expression of a mammalian histamine H₄ receptorprotein, inhibitors of polymorphonuclear leukocyte activation in vivo orin vitro, or combinations of the above, and corresponding methods oftreatment, prophylaxis, and diagnosis comprising the use of a disclosedcompound.

The terms “unit dose” and their grammatical equivalent forms are usedherein to refer to physically discrete units suitable as unitary dosagesfor human patients and other animals, each unit containing apredetermined effective, pharmacologic amount of the active ingredientcalculated to produce the desired pharmacological effect. Thespecifications for the novel unit dosage forms of this invention aredetermined by, and are directly dependent on, the characteristics of theactive ingredient, and on the limitations inherent in the art ofcompounding such an active ingredient for therapeutic use in humans andother animals.

The pharmaceutical compositions can be prepared using conventionalpharmaceutical excipients and compounding techniques. Examples ofsuitable unit dosage forms are tablets, capsules, pills, powders, powderpackets, granules, wafers, and the like, segregated multiples of anyunit dosage form, as well as liquid solutions, and suspensions. Someliquid forms are aqueous, whereas other embodiments of liquid forms arenon-aqueous. Oral dosage forms may be elixirs, syrups, capsules, tabletsand the like. Examples of solid carriers include those materials usuallyemployed in the manufacture of pills or tablets, such as lactose,starch, glucose, methylcellulose, magnesium stearate, dicalciumphosphate, mannitol and the like, thickeners such as tragacanth andmethylcellulose USP, finely divided SiO₂, polyvinylpyrrolidone,magnesium stearate, and the like. Typical liquid oral excipients includeethanol, glycerol, water and the like. All excipients may be mixed asneeded with diluents (for example, sodium and calcium carbonates, sodiumand calcium phosphates, and lactose), disintegrants (for example,cornstarch and alginic acid), granulating agents, lubricants (forexample, magnesium stearate, stearic acid, and talc), binders (forexample, starch and gelatin), thickeners (for example, paraffin, waxes,and petrolatum), flavoring agents, coloring agents, preservatives, andthe like by conventional techniques known to those of ordinary skill inthe art of preparing dosage forms. Coatings can be present and include,for example, glyceryl monostearate and/or glyceryl diestearate. Capsulesfor oral use include hard gelatin capsules in which the activeingredient is mixed with a solid diluent, and soft gelatin capsules, inwhich the active ingredient is mixed with water or an oil, such aspeanut oil, liquid paraffin, or olive oil.

Parenteral dosage forms may be prepared using water or another sterilecarrier. Parenteral solutions can be packaged in containers adapted forsubdivision into individual doses. For intramuscular, intraperitoneal,subcutaneous, and intravenous use, the compounds of the invention willgenerally be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity. Suitable aqueous vehiclesinclude Ringer's solution and isotonic sodium chloride. Aqueoussuspensions may include suspending agents such as cellulose derivatives,sodium alginate, polyvinyl-pyrrolidone, and gum tragacanth, and awetting agent, such as lecithin. Suitable preservatives for aqueoussuspensions include ethyl and n-propyl p-hydroxybenzoate. Parenteralformulations include pharmaceutically acceptable aqueous or non-aqueoussolutions, dispersion, suspensions, emulsions, and sterile powders forthe preparation thereof. Examples of carriers include water, ethanol,polyols (propylene glycol, polyethylene glycol), vegetable oils, andinjectable organic esters such as ethyl oleate. Fluidity can bemaintained by the use of a coating such as lecithin, a surfactant, ormaintaining appropriate particle size. Carriers for solid dosage formsinclude (a) fillers or extenders, (b) binders, (c) humectants, (d)disintegrating agents, (e) solution retarders, (f) absorptionaccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and(j) propellants.

Compositions may also contain adjuvants such as preserving, wetting,emulsifying, and dispensing agents; antimicrobial agents such asparabens, chlorobutanol, phenol, and sorbic acid; isotonic agents suchas a sugar or sodium chloride; absorption-prolonging agents such asaluminum monostearate and gelatin; and absorption-enhancing agents.

Physiologically acceptable carriers are well known in the art. Examplesof liquid carriers are solutions in which compounds according to thepresent invention form solutions, emulsions, and dispersions. Compatibleantioxidants, such as methylparaben and propylparaben, can be present insolid and/or liquid compositions, as can sweeteners.

Pharmaceutical compositions according to the present invention mayinclude suitable emulsifiers typically used in emulsion compositions.Such emulsifiers are described in standard publications such as H. P.Fiedler, 1989, Lexikon der Hilfsstoffe für Pharmazie, Kosmetic undagrenzende Gebiete, Cantor ed., Aulendorf, Germany, and in Handbook ofPharmaceutical Excipients, 1986, American Pharmaceutical Association,Washington, D.C., and the Pharmaceutical Society of Great Britain,London, UK, which are incorporated herein by reference. Gelling agentsmay also be added to compositions according to this invention.Polyacrylic acid derivatives, such as carbomers, are examples of gellingagents, and more particularly, various types of carbopol, which aretypically used in amounts from about 0.2% to about 2%. Suspensions maybe prepared as a cream, an ointment, including a water-free ointment, awater-in-oil emulsion, an oil-in-water emulsion, an emulsion gel, or agel.

It is anticipated that the compounds of the invention can beadministered by oral or parenteral routes, including intravenous,intramuscular, intraperitoneal, subcutaneous, rectal, intracisternal,intravaginal, intravesical, topical or local administration, and byinhalation (bucal or nasal, preferably in the form of a spray). For oraladministration, the compounds of the invention will generally beprovided in the form of tablets, capsules, or as a solution orsuspension. Other methods of administration include controlled releaseformulations, such as subcutaneous implants and dermal patches.

Effective doses of the compounds of the present invention may beascertained by conventional methods. The specific dosage level requiredfor any particular patient will depend on a number of factors, includingseverity of the condition, type of symptoms needing treatment, the routeof administration, the weight, age, and general condition of thepatient, and the administration of other medicaments.

In general, it is anticipated that the daily dose (whether administeredas a single dose or as divided doses) will be in the range from about0.01 mg to about 1000 mg per day, more usually from about 1 mg to about500 mg per day, and most usually form about 10 mg to about 200 mg perday. Expressed as dosage per unit body weight, a typical dose will beexpected to be between about 0.0001 mg/kg and about 15 mg/kg, especiallybetween about 0.01 mg/kg and about 7 mg/kg, and most especially betweenabout 0.15 mg/kg and 2.5 mg/kg.

Anticipated oral dose ranges include from about 0.01 to 500 mg/kg,daily, more preferably from about 0.05 to about 100 mg/kg, taken in 1-4separate doses. Some compounds of the invention may be orally dosed inthe range of about 0.05 to about 50 mg/kg daily, while others may bedosed at 0.05 to about 20 mg/kg daily. Infusion doses can range fromabout 1.0 to about 1.0×10⁴ μg/(kg.min) of inhibitor, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days. For topical administration, compounds of the presentinvention may be mixed with a pharmaceutical carrier at a concentrationfrom about 0.1 to about 10% of drug to vehicle. Capsules, tablets orother formulations (such as liquids and film-coated tablets) may be ofbetween 0.5 and 200 mg, such as 1, 3, 5, 10, 15, 25, 35, 50 mg, 60 mg,and 100 mg and can be administered according to the disclosed methods.Daily dosages are envisaged to be, for example, between 10 mg and 5000mg for an adult human being of normal weight.

EXAMPLES General Experimental

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz) orDPX500 (500 MHz) spectrometer. The format of the ¹H NMR data below is:chemical shift in ppm down field of the tetramethylsilane reference(multiplicity, coupling constant J in Hz, integration).

Mass spectra were obtained on a Hewlett Packard (Agilent) series 1100MSD using electrospray ionization (ESI) in either positive or negativemode as indicated. The “mass calculated” for a molecular formula is themonoisotopic mass of the compound.

Purification Method 1: Reversed-Phase HPLC

HPLC retention times are reported in minutes, using the methods andconditions reported below.

Instrument: Agilent HP-1100

Solvent: Acetonitrile (0.05% TFA)/H₂O (0.05% TFA)

Flow rate: 0.75 mL/min

Gradient: 1 min at 1% H₂O; 7 min linear ramp to 99% H₂O;

-   -   4 min at 99% H₂O.        Column: Zorbax Eclipse XDB-C8 (5 um, 4.6×150 mm)        Temperature: 35° C.        Wavelength: Dual detection at 220 nM and 254 nM.        Purification Method 2: Normal-Phase Chromatography

2-Arylbenzimidazoles were purified by chromatography on silica geleluting with dichloromethane, then 10% methanol in dichloromethane, andsubsequently 10% (2.0 M ammonia in methanol) in dichloromethane. Thereaction mixtures were loaded on the silica gel without work-up.

Example 1

2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,5-dimethyl-1H-benzoimidazole

General Procedure 1

A. 2-Chloro-4-(3-chloro-propoxy)-benzaldehyde. 1-Bromo-3-chloropropane(2.55 g, 16.2 mmol, 1.0 equiv) was added to a solution of the2-chloro-4-hydroxybenzaldehyde (2.54 g, 16.2 mmol, 1.0 equiv) and K₂CO₃(4.48 g, 32.4 mmol, 2.0 equiv) in acetonitrile (41 mL). The mixture washeated at 65° C. for 18 h, then cooled to room temperature (rt) andfiltered through diatomaceous earth. The filtrate was concentrated underreduced pressure yielding crude product, which was purified by columnchromatography (silica gel, 5% ethyl acetate in hexanes) to afford 3.19g of a colorless oil (66%). ¹H NMR (400 MHz, CD₃OD): 10.3 (s, 1H), 7.87(d, J=8.0 Hz, 1H), 7.10 (d, J=4.0 Hz, 1H), 7.03 (dd, J=8.0, 4.0 Hz, 1H),4.23 (t, J=8.0 Hz, 2H), 3.76 (t, J=8.0 Hz, 2H), 2.31-2.22 (m, 2H).

General Procedure 2.

B. 2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde.N-Methylpiperazine (2.16 g, 21.5 mmol, 2.0 equiv),2-chloro-4-(3-chloro-propoxy)-benzaldehyde (3.19 g, 10.8 mmol, 1.0equiv), K₂CO₃ (4.46 g, 32.3 mmol, 3.0 equiv), and KI (1.02 g, 5.38 mmol,0.5 equiv) were stirred in n-butanol (22 mL) at 90° C. for 18 h. Thereaction mixture was diluted with water and then extracted three timeswith ethyl acetate. The combined extracts were dried (Na₂SO₄), filtered,and concentrated, yielding the crude product, which was purified byMethod 2 to afford 2.04 g (63%) of an orange oil. ¹H NMR (400 MHz,CD₃OD): 10.3 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H),7.00 (dd, J=8.0, 2.0 Hz, 1H), 4.15 (t, J=8.0 Hz, 2H), 3.00-2.30 (br s,10H), 2.29 (s, 3H), 2.05-1.90 (m, 2H).

General Procedure 3.

C.2-{(2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,5-dimethyl-1H-benzoimidazole.2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (91.5 mg,0.31 mmol, 1.0 equiv) and 3,4-dimethyl-benzene-1,2-diamine (42 mg, 0.31mmol, 1.0 equiv) were stirred with Na₂S₂O₅ (76 mg, 0.40 mmol, 1.3 equiv)in DMF (0.25 M) at 90° C. for 12 h. The reaction mixture was loadeddirectly on silica gel and purified according to Method 2, whichafforded 98 mg (76%) of the title compound. MS (electrospray): masscalculated for C₂₃H₂₉ClN₄O, 412.20; m/z found, 413.4 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 7.68 (br s, 1H), 7.33 (br s, 1H), 7.15 (d, J=2.5 Hz, 1H),7.07 (d, J=8.7, 2.5 Hz, 1H), 7.03 (dd, J=8.7, 2.5 Hz, 1H), 4.13 (t,J=6.1 Hz, 2H), 2.60-2.39 (m, 13H), 2.39 (s, 3H), 2.30 (s, 3H), 2.05-1.95(m, 2H).

Example 2

2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole

A. 3-(1-Methyl-piperidin-4-yl)-propan-1-ol. To a refluxing solution of 1N lithium aluminum hydride in THF (40 mmol) was added dropwise asolution of N—BOC-4-piperidinepropionic acid (3.0 g, 11.6 mmol) in THF(30 mL). The reaction mixture was heated for 3 h and then cooled to rt.Upon further cooling to 0° C., water (1.5 mL) was added slowly, and thereaction mixture was allowed to warm to rt over 15 min. The mixture wasagain cooled to 0° C., and 10% NaOH (1.5 mL) was added slowly. Uponwarming up to rt over 15 min, the mixture was again cooled to 0° C. andmore water (4.5 mL) was added. The resultant mixture was allowed to warmto rt over 18 h, and was then filtered through a diatomaceous earth pad.The filtrate was concentrated under reduced pressure, and the residuewas purified by Method 2 to afford 1.9 g (100%) of3-(1-methyl-piperidin-4-yl)-propan-1-ol as a yellow oil. MS(electrospray): mass calculated for C₉H₁₉NO, 157.15; m/z found, 158.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 3.45-3.41 (m, 2H), 2.77-2.74 (m, 2H),1.89-1.85 (m, 2H), 1.64-1.61 (m, 2H), 1.47-1.43 (m, 2H), 1.21-1.12 (m,5H).

B. 2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde. To anice-cooled solution of 2-chloro-4-hydroxybenzaldehyde (507 mg, 3.2 mmol,1.0 equiv), triphenylphosphine (1.02 g, 3.9 mmol, 1.2 equiv), and3-(1-methyl-piperidin-4-yl)-propan-1-ol (508 mg, 3.9 mmol, 1.2 equiv) inTHF (15 mL) was added diethyl azodicarboxylate (DEAD; 0.6 mL, 3.2 mmol,1.0 equiv). The reaction mixture was allowed to warm to rt and wasstirred for 16 h. The mixture was diluted with water and extracted threetimes with ethyl acetate. The combined extracts were dried (Na₂SO₄) andconcentrated. Purification by Method 2 afforded 768 mg (80%) of thedesired aldehyde. MS (electrospray): mass calculated for C₁₆H₂₃NO₂,261.17; m/z found, 262.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 9.85 (s, 1H),7.80 (d, J=8.6 Hz, 2H), 6.97 (d, J=8.6 Hz, 2H), 4.01 (t, J=6.4 Hz, 2H),2.84-2.82 (m, 2H), 2.25 (s, 3H), 1.92-1.78 (m, 4H), 1.71-1.69 (m, 2H),1.41-1.37 (m, 2H), 1.29-1.26 (m, 3H).

C.2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole.2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde and3-methyl-benzene-1,2-diamine were stirred with Na₂S₂O₅ in DMF at 90° C.for 12 h. Purification of the reaction mixture by Method 2 afforded 129mg (73%) of the title compound. MS (electrospray): mass calculated forC₂₃H₂₈ClN₃O, 397.19; m/z found, 398.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):7.69 (d, J=8.5 Hz, 1H), 7.46-7.35 (m, 1H), 7.17-7.13 (m, 2H), 7.06-7.01(m, 2H), 4.06 (t, J=6.4 Hz, 2H), 2.95-2.85 (m, 2H), 2.59 (s, 3H), 2.27(s, 3H), 2.10-1.95 (m, 2H), 1.86-1.76 (m, 4H), 1.50-1.49 (m, 2H),1.32-1.25 (m, 3H).

Example 3

2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethoxy-1H-benzoimidazole

This compound was prepared by the method described in General Procedure3 using 2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde(200 mg, 0.68 mmol, 1.0 equiv), 4-trifluoromethoxy-benzene-1,2-diamine(119 mg, 0.62 mmol, 0.92 equiv) and Na₂S₂O₅ (167 mg, 0.88 mmol, 1.3equiv). Purification by Method 2 afforded 72 mg (23%) of the titlecompound. MS (electrospray): mass calculated for C₂₂H₂₄ClF₃N₄O₂, 468.15;m/z found, 469.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.82 (d, J=8.7 Hz,1H), 7.69 (d, J=8.8 Hz, 1H), 7.55 (s, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.21(d, J=1.6 Hz, 1H), 7.1 (dd, J=8.6, 2.2 Hz, 1H), 4.17 (t, J=5.7 Hz, 2H),2.88-2.38 (m, 10H), 2.32 (s, 3H), 2.10-1.95 (m, 2H).

Example 4

5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

This compound was prepared by the method described in Example 1, using3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-benzaldehyde (62mg, 0.20 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (33 mg, 0.20mmol, 1.0 equiv), and Na₂S₂O₅ (50 mg, 0.26 mmol, 1.3 equiv) in GeneralProcedure 3. Purification by Method 2 afforded 31 mg (34%) of the titlecompound. MS (electrospray): mass calculated for C₂₆H₃₅ClN₄O, 454.25;m/z found, 455.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.12 (d, J=2.2 Hz,1H), 7.98 (dd, J=8.6, 2.3 Hz, 1H), 7.6 (s, 1H), 7.52 (d, J=8.5 Hz, 1H),7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 4.19 (t, J=6.0 Hz,2H), 2.84-2.74 (m, 10H), 2.40 (s, 3H), 2.08-1.97 (m, 2H), 1.90-1.83 (m,2H), 1.41 (s, 9H).

Example 5

5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

This compound was prepared by the method described in Example 2, using3-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde (98.6 mg,0.36 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (59 mg, 0.36mmol, 1.0 equiv), and Na₂S₂O₅ (89 mg, 0.47 mmol, 1.3 equiv) in Step C.Purification by Method 2 afforded 116 mg (77%) of the title compound. MS(electrospray): mass calculated for C₂₇H₃₇N₃O, 419.29; m/z found, 420.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.90-7.82 (m, 2H), 7.60-7.50 (m, 1H),7.52-7.40 (m, 1H), 7.33 (dd, J=8.5, 1.8 Hz, 1H), 7.02 (d, J=9.1 Hz, 1H),4.07 (t, J=6.2 Hz, 2H), 2.92-2.85 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H),2.10-2.00 (m, 2H), 1.90-1.80 (m, 2H), 1.80-1.70 (m, 2H), 1.55-1.45 (m,2H), 1.49 (s, 9H), 1.49-1.26 (m, 3H).

Example 6

4,5-Dimethyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

This compound was prepared by the method described in Example 1, using3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (180 mg,0.65 mmol, 1.0 equiv), 3,4-dimethyl-benzene-1,2-diamine (89 mg, 0.65mmol, 1.0 equiv), and Na₂S₂O₅ (161 mg, 0.85 mmol, 1.3 equiv) in GeneralProcedure 3. Purification by Method 2 afforded 192 mg (75%) of the titlecompound. MS (electrospray): mass calculated for C₂₄H₃₂N₄O, 392.26; m/zfound, 393.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.95-7.85 (m, 2H),7.35-7.23 (m, 1H), 7.08-7.00 (m, 2H), 4.12 (t, J=6.0 Hz, 2H), 2.64-2.37(m, 16H), 2.29 (s, 6H), 2.10-2.00 (m, 2H).

Example 7

5-tert-Butyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimidazole

This compound was prepared by the method described in Example 1, using3-[4-(4-methyl-piperazin-1-yl)-butoxy]-benzaldehyde (53 mg, 0.19 mmol,1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (32 mg, 0.19 mmol, 1.0equiv), and Na₂S₂O₅ (48 mg, 0.25 mmol, 1.3 equiv) in General Procedure3. Purification by Method 2 afforded 75 mg (92%) of the title compound.MS (electrospray): mass calculated for C₂₆H₃₆N₄O, 420.29; m/z found,421.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.68-7.56 (m, 3H), 7.54 (br d,J=8.2 Hz, 1H), 7.44-7.36 (m, 2H), 7.02 (dd, J=8.2, 2.2 Hz, 1H), 4.07 (t,J=6.1 Hz, 2H), 3.00-2.26 (m, 10H), 2.26 (s, 3H), 1.85-1.75 (m, 2H),1.75-1.65 (m, 2H), 1.40 (s, 9H).

Example 8

5-tert-Butyl-2-{3-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-phenyl}-1H-benzoimidazole

A. 3-(4-Chloro-butoxy)-benzaldehyde. This intermediate was prepared bythe method described in General Procedure 1 using 3-hydroxybenzaldehyde(2.0 g, 16.4 mmol, 1.0 equiv), 1-bromo-4-chlorobutane (1.62 mL, 16.4mmol, 1.0 equiv), and K₂CO₃ (4.53 g, 33 mmol, 1.0 equiv). Purificationafforded 2.57 g (79%) of the desired product. ¹H NMR (400 MHz, CDCl₃):9.98 (s, 1H), 7.47-7.43 (m, 2H), 7.40-7.37 (m, 1H), 7.27-7.25 (m, 1H),4.09-4.03 (m, 2H), 3.66-3.58 (m, 2H), 2.03-1.93 (m, 4H).

B. 5-tert-Butyl-2-[3-(4-chloro-butoxy)-phenyl]-1H-benzoimidazole. Thisintermediate was prepared by the method described in General Procedure 3using 3-(4-chloro-butoxy)-benzaldehyde (500 mg, 2.52 mmol, 1.0 equiv),4-tert-butyl-benzene-1,2-diamine (414 mg, 2.52 mmol, 1.0 equiv), andNa₂S₂O₅ (622 mg, 3.3 mmol, 1.3 equiv). The reaction mixture was loadedon a silica gel column and purified by flash chromatography (25% ethylacetate in hexanes) to afford 348 mg (40%) of the desired product. ¹HNMR (400 MHz, CDCl₃): 7.72-7.48 (m, 4H), 7.47-7.35 (m, 2H), 7.08-7.03(m, 1H), 4.17-4.10 (m, 2H), 3.70-3.64 (m, 2H), 2.03-1.96 (m, 4H), 1.41(s, 9H).

C.5-tert-Butyl-2-{3-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-phenyl}-1H-benzoimidazole.This compound was prepared by the method described in General Procedure2 using 5-tert-butyl-2-[3-(4-chloro-butoxy)-phenyl]-1H-benzoimidazole(51.2 mg, 0.15 mmol, 1.0 equiv), N-methyl-homo-piperazine (19 μL, 0.15mmol, 1.0 equiv), K₂CO₃ (40 mg, 0.30 mmol, 2.0 equiv), and KI (12 mg,0.08 mmol, 0.5 equiv). Purification by Method 2 afforded 19 mg (23%) ofthe title compound. MS (electrospray): mass calculated for C₂₇H₃₈N₄O,434.30; m/z found, 435.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.66-7.62 (m,3H), 7.52 (d, J=8.6 Hz, 1H), 7.45-7.35 (m, 1H), 7.37 (dd, J=8.6, 1.8 Hz,1H), 7.06-7.02 (m, 1H), 4.11 (t, J=6.2 Hz, 2H), 2.78-2.75 (m, 4H),2.69-2.65 (m, 4H), 2.60-2.55 (m, 2H), 2.32 (s, 3H), 1.85-1.79 (m, 4H),1.75-1.68 (m, 2H), 1.40 (s, 9H).

Example 9

(1-{3-[4-(5-tert-Butyl-1H-benzoimidazol-2-yl)-2-chloro-phenoxy]-propyl}-pyrrolidin-3-yl)-dimethylamine

This compound was prepared by the method described in Example 1, using5-tert-butyl-2-[3-(4-chloro-butoxy)-phenyl]-1H-benzoimidazole (206 mg,0.55 mmol, 1.0 equiv), dimethyl-pyrrolidin-3-yl-amine (125 mg, 1.09mmol, 2.0 equiv), K₂CO₃ (227 mg, 1.64 mmol, 3.0 equiv), and KI (46 mg,0.27 mmol, 0.5 equiv) in General Procedure 3. Purification by Method 2afforded 137 mg (55%) of the title compound. MS (electrospray): masscalculated for C₂₆H₃₅ClN₄O, 454.25; m/z found, 455.5 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 8.11 (d, J=2.2 Hz, 1H), 7.97 (dd, J=8.6, 2.2 Hz, 1H), 7.58(br s, 1H), 7.65-7.45 (m, 1H), 7.36 (dd, J=8.6, 1.7 Hz, 1H), 7.24 (d,J=8.7 Hz, 1H), 4.21 (t, J=6.0 Hz, 2H), 3.04-2.99 (m, 1H), 2.91-2.65 (m,4H), 2.56-2.49 (m, 1H), 2.36-2.29 (m, 1H), 2.24 (s, 6H), 2.10-1.99 (m,3H), 1.79-1.70 (m, 1H), 1.40 (s, 9H).

Example 10

5-Chloro-2-{3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-6-methyl-1H-benzoimidazole

This compound was prepared by the method described in Example 1, using3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-benzaldehyde (61mg, 0.20 mmol, 1.0 equiv), 4-chloro-5-methyl-benzene-1,2-diamine (31 mg,0.20 mmol, 1.0 equiv), and Na₂S₂O₅ (48 mg, 0.25 mmol, 1.3 equiv) inGeneral Procedure 3. Purification by Method 2 afforded 7.1 mg (8%) ofthe title compound. MS (electrospray): mass calculated for C₂₃H₂₈Cl₂N₄O,446.16; m/z found, 447.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.96 (d, J=2.2Hz, 1H), 7.83 (dd, J=8.6, 2.2 Hz, 1H), 7.45 (s, 1H), 7.34 (s, 1H), 7.10(d, J=8.7 Hz, 1H), 4.08 (t, J=6.0 Hz, 2H), 2.76-2.64 (m, 10H), 2.36 (s,3H), 2.30 (s, 3H), 1.96-1.88 (m, 2H), 1.80-1.73 (m, 2H).

Example 11

2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole

This compound was prepared by the method described in Example 1, using3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (94 mg,0.34 mmol, 1.0 equiv), 3-methyl-benzene-1,2-diamine (42 mg, 0.34 mmol,1.0 equiv), and Na₂S₂O₅ (84 mg, 0.44 mmol, 1.3 equiv) in GeneralProcedure 3. Purification by Method 2 afforded 130 mg (100%) of thetitle compound. MS (electrospray): mass calculated for C₂₂H₂₇FN₄O,382.22; m/z found, 383.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.86-7.78 (m,2H), 7.40-7.37 (m, 1H), 7.12-6.97 (m, 3H), 3.99 (t, J=6.1 Hz, 2H),3.00-2.30 (m, 13H), 2.25 (s, 3H), 1.94-1.90 (m, 2H).

Example 12

5-Methyl-2-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-naphthalen-1-yl}-1H-benzoimidazole

This compound was prepared by the method described in Example 1, using4-[3-(4-methyl-piperazin-1-yl)-propoxy]-naphthalene-1-carbaldehyde (63mg, 0.20 mmol, 1.0 equiv), 4-methyl-benzene-1,2-diamine (24 mg, 0.20mmol, 1.0 equiv), and Na₂S₂O₅ (49 mg, 0.26 mmol, 1.3 equiv) in GeneralProcedure 3. The desired product was isolated from the reaction mixtureusing Method 1 and was subsequently re-purified by Method 2 to afford54.6 mg (66%) of the title compound. MS (electrospray): mass calculatedfor C₂₆H₃₀N₄O, 414.24; m/z found, 415.62 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): 8.48 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 8.0 (d, J=8.2Hz, 1H), 7.78-7.65 (m, 4H), 7.50 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.2 Hz,1H), 4.43 (t, J=6.0 Hz, 2H), 3.40 (br s, 4H), 3.30-3.00 (m, 6H), 2.88(s, 3H), 2.59 (s, 3H), 2.36-2.30 (m, 2H).

Example 13

4-[3-(5-tert-Butyl-1H-benzoimidazol-2-yl)-phenoxy]-1-(4-methyl-piperazin-1-yl)-butan-1-one

A. 3-[4-(4-Methyl-piperazin-1-yl)-4-oxo-butoxy]-benzaldehyde. To asolution of 4-(3-formyl-phenoxy)-butyric acid (981 mg, 4.72 mmol, 1.0equiv) and N-methylpiperazine (576 mg, 5.19 mmol, 1.1 equiv) indichloromethane at 0° C. was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI; 1.18 g, 6.14 mmol,1.3 equiv) and 1-hydroxybenzotriazole hydrate (HOBT; 701 mg, 5.19 mmol,1.1 equiv). The reaction mixture, which was allowed to warm to rt, wasstirred for 2.0 h and then poured into water. This mixture was extractedthree times with ethyl acetate. The combined extracts were dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The cruderesidue was purified by column chromatography (silica gel, 5% MeOH indichloromethane) to afford 847 mg (62%) of the desired product. ¹H NMR(400 MHz, CD₃OD): 9.72 (s, 1H), 7.29-7.23 (m, 2H), 7.22-7.19 (m, 1H),7.05-6.98 (m, 1H), 3.87 (t, J=6.1 Hz, 2H), 3.43-3.31 (m, 4H), 2.39 (t,J=7.2 Hz, 2H), 2.27-2.17 (m, 4H), 2.08 (s, 3H), 1.92-1.80 (m, 2H).

B.4-[3-(5-tert-Butyl-1H-benzoimidazol-2-yl)-phenoxy]-1-(4-methyl-piperazin-1-yl)-butan-1-one.This compound was prepared by the method described in General Procedure3 using 3-[4-(4-methyl-piperazin-1-yl)-4-oxo-butoxy]-benzaldehyde (81.2mg, 0.28 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (46 mg, 0.28mmol, 1.0 equiv), and Na₂S₂O₅ (69 mg, 0.36 mmol, 1.3 equiv).Purification by Method 2 afforded 77 mg (64%) of the title compound. MS(electrospray): mass calculated for C₂₆H₃₄N₄O₂, 434.27; m/z found, 435.0[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.69-7.62 (m, 3H), 7.54 (d, J=8.6 Hz,1H), 7.45-7.37 (m, 2H), 7.06 (dd, J=8.2, 2.2 Hz, 1H), 4.13 (t, J=6.1 Hz,2H), 3.70-3.50 (m, 4H), 2.62 (t, J=7.3 Hz, 2H), 2.49-2.40 (m, 4H), 2.32(s, 3H), 2.16-2.09 (m, 2H), 1.41 (s, 9H).

Example 14

5-Chloro-2-[3-chloro-4-(3-piperazin-1-yl-propoxy)-phenyl]-6-fluoro-1H-benzoimidazole

A.4-{3-[2-Chloro-4-(5-chloro-6-fluoro-1H-benzoimidazol-2-yl)-phenoxy]-propyl}-piperazine-1-carboxylicacid tert-butyl ester. This compound was prepared by the methoddescribed in Example 1, using4-[3-(2-chloro-4-formyl-phenoxy)-propyl]-piperazine-1-carboxylic acidtert-butyl ester (1.0 g, 2.6 mmol, 1.0 equiv),4-chloro-5-fluoro-benzene-1,2-diamine (421 mg, 2.6 mmol, 1.0 equiv), andNa₂S₂O₅ (648 mg, 3.4 mmol, 1.3 equiv) in General Procedure 3.Purification by Method 2 afforded 256 mg (15%) of the title compound. MS(electrospray): mass calculated for C₂₅H₂₉Cl₂FN₄O₃, 522.16; m/z found,545.3 [M+Na]⁺.

B.5-Chloro-2-[3-chloro-4-(3-piperazin-1-yl-propoxy)-phenyl]-6-fluoro-1H-benzoimidazole.To a suspension of4-{3-[2-chloro-4-(5-chloro-6-fluoro-1H-benzoimidazol-2-yl)-phenoxy]-propyl}-piperazine-1-carboxylicacid tert-butyl ester (52.7 mg, 0.10 mmol) in dichloromethane (1.0 mL)at rt was added TFA (1.0 mL), and the reaction mixture was stirred for50 min. The mixture was concentrated under reduced pressure, and thesolid residue was washed four times with dichloromethane. The titlecompound was obtained in quantitative yield as the TFA salt. MS(electrospray): mass calculated for C₂₀H₂₁Cl₂FN₄O, 422.11; m/z found,423.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.17 (d, J=2.3 Hz, 1H), 8.03 (dd,J=8.7, 2.3 Hz, 1H), 7.81 (d, J=6.4 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.36(d, J=8.8 Hz, 1H), 4.33 (t, J=5.8 Hz, 2H), 3.50-3.47 (m, 4H), 3.36 (brs, 4H), 3.25 (t, J=7.4 Hz, 2H), 2.33-2.26 (m, 2H).

Example 15

5-tert-Butyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

This compound was prepared by the method described in Example 1, using3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (516 mg,1.87 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (307 mg, 1.87mmol, 1.0 equiv), and Na₂S₂O₅ (461 mg, 2.43 mmol, 1.3 equiv) in GeneralProcedure 3. Purification by Method 2 afforded 633 mg (81%) of the titlecompound. MS (electrospray): mass calculated for C₂₆H₃₆N₄O, 420.29; m/zfound, 421.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.90-7.85 (m, 2H),7.65-7.40 (m, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H),4.14-4.11 (m, 2H), 2.90-2.28 (m, 16H), 2.06-2.03 (m, 2H), 1.39 (s, 9H).

Example 16

2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,6-dimethyl-1H-benzoimidazole

This compound was prepared by the method described in Example 2, using2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde (106 mg,0.36 mmol, 1.0 equiv), 3,5-dimethyl-benzene-1,2-diamine (49 mg, 0.36mmol, 1.0 equiv), and Na₂S₂O₅ (88 mg, 0.47 mmol, 1.3 equiv) in Step C.Purification by Method 2 afforded 128 mg (87%) of the title compound. MS(electrospray): mass calculated for C₂₄H₃₀ClN₃O, 411.21; m/z found,412.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.68 (d, J=8.5 Hz, 1H), 7.21 (brs, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.01 (dd, J=8.7, 2.5 Hz, 1H), 6.90 (s,1H), 4.05 (t, J=6.3 Hz, 2H), 2.92-2.88 (m, 2H), 2.54 (s, 3H), 2.43 (s,3H), 2.29 (s, 3H), 2.09-2.03 (m, 2H), 1.85-1.76 (m, 4H), 1.47-1.11 (m,5H).

The following compounds in Examples 17-56 were prepared using GeneralProcedures 1, 2, and 3 as exemplified above.

Example 17

2-{2-Chloro-4-[2-methyl-3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₉ClN₄O, 412.20; m/z found,413.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.75-7.65 (m, 1H), 7.50-7.35 (m,1H), 7.20-7.13 (m, 2H), 7.15-7.02 (m, 2H), 4.06 (dd, J=9.2, 4.5 Hz, 1H),3.94 (dd, J=9.2, 6.0 Hz, 1H), 2.80-2.35 (m, 13H), 2.35-2.20 (m, 4H),2.28 (d, J=4.5 Hz, 3H).

Example 18

5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₆Cl₂N₄O, 432.15; m/z found,432.8 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.19 (d, J=2.2 Hz, 1H), 8.05 (dd,J=8.6, 2.2 Hz, 1H), 7.66 (br s, 1H), 7.55 (br s, 1H), 7.32 (d, J=8.7 Hz,1H), 4.30 (t, J=6.0 Hz, 2H), 3.00-2.43 (m, 13H), 2.42 (s, 3H), 2.18-2.14(m, 2H).

Example 19

6-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₆Cl₂N₄O, 432.15; m/z found,433.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.70 (br s, 1H), 7.42 (br s, 1H),7.17 (d, J=2.4 Hz, 1H), 7.08 (br s, 1H), 7.05 (dd, J=8.7, 2.5 Hz, 1H),4.13 (t, J=6.14 Hz, 2H), 3.00-2.40 (m, 13H), 2.30 (s, 3H), 2.03-1.98 (m,2H).

Example 20

5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₅H₃₃ClN₄O, 440.23; m/z found,441.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.31 (d, J=2.2 Hz, 1H), 8.17 (dd,J=8.6, 2.2 Hz, 1H), 7.78 (br s, 1H), 7.69 (br s, 1H), 7.55 (dd, J=8.6,1.7 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 4.40 (t, J=6.0 Hz, 2H), 3.00-2.55(m, 10H), 2.51 (s, 3H), 2.35-2.22 (m, 2H), 1.59 (s, 9H).

Example 21

5-Chloro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₁H₂₄ClFN₄O, 402.16; m/z found,403.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.86-7.83 (m, 2H), 7.64 (d, J=1.9Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.39 (dd, J=8.7, 1.9 Hz, 1H), 7.33-7.29(m, 1H), 4.21 (t, J=5.9 Hz, 2H), 3.20-2.77 (m, 10H), 2.76 (s, 3H),2.10-2.03 (m, 2H).

Example 22

2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,6-dimethyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₁ClN₄O, 426.22; m/z found,427.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.58 (d, J=8.6 Hz, 1H), 7.11 (s,1H), 7.03 (d, J=2.5 Hz, 1H), 6.91 (dd, J=8.7, 2.5 Hz, 1H), 6.80 (s, 1H),3.99 (t, J=6.1 Hz, 2H), 2.75-2.58 (m, 10H), 2.45 (s, 3H), 2.32 (s, 3H),2.30 (s, 3H), 1.89-1.85 (m, 2H), 1.78-1.74 (m, 2H).

Example 23

5-Chloro-6-methyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₉ClN₄O, 412.20; m/z found,413.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.60-7.56 (m, 3H), 7.44-7.37 (m,2H), 7.03-7.00 (m, 1H), 4.05 (t, J=6.1 Hz, 2H), 3.00-2.30 (m, 13H), 2.27(s, 3H), 1.82-1.73 (m, 2H), 1.72-1.67 (m, 2H). ¹³C NMR (TFA salt, 100MHz, CD₃OD): 161.0, 154.0, 138.5, 131.9, 131.7, 131.3, 130.2, 120.0,118.2, 116.7, 116.2, 113.4, 68.7, 58.0, 54.2, 51.7, 44.2, 27.8, 23.5,20.8.

Example 24

5-Chloro-6-fluoro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₁H₂₃ClF₂N₄O, 420.15; m/z found,421.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.80-7.75 (m, 2H), 7.66 (d, J=6.4Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.27 (t, J=9.3 Hz, 1H), 4.21 (t, J=8.0Hz, 2H), 3.25 (br s, 4H), 3.02 (br s, 4H), 2.90 (t, J=7.8 Hz, 2H), 2.81(s, 3H), 2.12-2.05 (m, 2H).

Example 25

2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₇FN₄O, 382.22; m/z found,383.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.85-7.80 (m, 2H), 7.57 (d, J=8.4Hz, 1H), 7.49 (s, 1H), 7.38-7.34 (m, 2H), 4.22 (t, J=5.9 Hz, 2H), 3.24(br s, 4H), 2.95 (br s, 4H), 2.84 (t, J=7.2 Hz, 2H), 2.77 (s, 3H), 2.46(s, 3H), 2.12-2.05 (m, 2H).

Example 26

5,6-Difluoro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₁H₂₃F₃N₄O, 404.18; m/z found,405.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.79-7.73 (m, 2H), 7.50-7.45 (m,2H), 7.28-7.22 (m, 1H), 4.18 (t, J=5.9 Hz, 2H), 3.04-2.83 (m, 10H), 2.76(s, 3H), 2.10-2.03 (m, 2H).

Example 27

2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₁H₂₅FN₄O, 368.20; m/z found,369.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.88-7.81 (m, 2H), 7.71-7.66 (m,2H), 7.52-7.48 (m, 2H), 7.37 (t, J=8.8 Hz, 1H), 4.22 (t, J=6.0 Hz, 2H),3.04-2.76 (m, 13H), 2.10-2.03 (m, 2H).

Example 28

2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,5-dimethyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₁ClN₄O, 426.22; m/z found,427.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.75-7.65 (m, 1H), 7.40-7.25 (m,1H), 7.15 (d, J=2.5 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.04 (dd, J=8.6,2.5 Hz, 1H), 4.13 (t, J=6.1 Hz, 1H), 2.85-2.70 (m, 10H), 2.51 (br s,3H), 2.42 (s, 3H), 2.40 (s, 3H), 2.02-1.96 (m, 2H), 1.88-1.86 (m, 2H).¹³C NMR (100 MHz, CD₃OD): 13.7, 19.4, 24.2, 26.9, 45.0, 50.9, 54.7,55.4, 55.9, 56.6, 67.4, 112.2, 115.2, 117.7, 118.9, 123.7, 128.8, 133.6,134.5, 134.7, 135.2, 135.5, 148.9, 163.5.

Example 29

5,6-Dimethyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=5.96. MS (electrospray): mass calculated for C₂₄H₃₂N₄O,392.26; m/z found, 393.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.57-7.50 (m,3H), 7.48 (s, 2H), 7.23-7.20 (m, 1H), 4.08 (t, J=5.8 Hz, 2H), 3.16 (brs, 4H), 3.01 (br s, 4H), 2.82-2.79 (m, 2H), 2.71 (s, 3H), 2.38 (s, 6H),1.85-1.74 (m, 4H).

Example 30

2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,6-dimethyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₉ClN₄O, 412.20; m/z found,413.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.68 (d, J=8.5 Hz, 1H), 7.21 (brs, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.03 (dd, J=8.7, 2.5 Hz, 1H), 6.90 (s,1H), 4.13 (t, J=6.2 Hz, 2H), 2.70-2.40 (m, 16H), 2.96 (s, 3H), 2.06-1.98(m, 2H).

Example 31

2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₉ClN₄O, 412.20; m/z found,413.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.72-7.69 (m, 1H), 7.50-7.35 (m,1H), 7.18-7.13 (m, 2H), 7.06-7.03 (m, 2H), 4.14 (t, J=6.1 Hz, 2H),2.85-2.70 (m, 10H), 2.59 (s, 3H), 2.40 (s, 3H), 2.02-1.96 (m, 2H),1.89-1.85 (m, 2H).

Example 32

5-tert-Butyl-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₅H₃₃ClN₄O, 440.23; m/z found,441.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.76 (d, J=8.7 Hz, 1H), 7.62-7.53(m, 2H), 7.38 (dd, J=8.6, 2.0 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.04 (dd,J=8.7, 2.5 Hz, 1H), 4.13 (t, J=6.1 Hz, 2H), 2.80-2.20 (m, 13H),2.06-1.96 (m, 2H), 1.40 (s, 9H)

Example 33

2-{3-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethyl-1H-benzoimidazole

HPLC: R_(t)=6.30. MS (electrospray): mass calculated for C₂₃H₂₇F₃N₄O₂,448.21; m/z found, 449.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.93 (s, 1H),7.79 (d, J=8.6 Hz, 1H), 7.69-7.66 (m, 3H), 7.11 (d, J=9.0 Hz, 1H), 4.16(t, J=5.6 Hz, 2H), 3.90 (s, 3H), 3.45-3.39 (m, 7H), 3.21-3.18 (m, 3H),3.18 (s, 3H), 2.21-2.17 (m, 2H).

Example 34

5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-fluoro-1H-benzoimidazole

HPLC: R_(t)=6.41. MS (electrospray): mass calculated for C₂₁H₂₃Cl₂FN₄O,436.12; m/z found, 437.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.98 (d, J=2.3Hz, 1H), 7.87 (dd, J=8.7, 2.3 Hz, 1H), 7.63 (d, J=6.4 Hz, 1H), 7.41 (d,J=8.8 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 4.19 (t, J=5.7 Hz, 2H), 3.39 (brs, 4H), 3.25-3.20 (m, 4H), 3.09 (t, J=7.3 Hz, 2H), 2.83 (s, 3H),2.19-2.15 (m, 2H).

Example 35

5,6-Dichloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.64. MS (electrospray): mass calculated for C₂₁H₂₃Cl₃N₄O,452.09; m/z found, 453.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.74 (s, 2H),7.60 (d, J=8.8 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 6.94 (dd, J=8.8, 2.4 Hz,1H), 4.00 (t, J=5.8 Hz, 2H), 3.43 (br s, 7H), 3.19 (t, J=7.7 Hz, 2H),3.05-3.04 (m, 1H), 2.74 (s, 3H), 2.10-2.02 (m, 2H).

Example 36

5-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.09. MS (electrospray): mass calculated for C₂₁H₂₄Cl₂N₄O,418.13; m/z found, 419.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.76 (d, J=8.8Hz, 1H), 7.73 (dd, J=1.9, 0.4 Hz, 1H), 7.69 (dd, J=8.8, 0.4 Hz, 1H),7.47 (dd, J=8.8, 1.9 Hz, 1H), 7.23 (d, J=2.5 Hz, 1H), 7.09 (dd, J=8.8,2.5 Hz, 1H), 4.15 (t, J=5.9 Hz, 2H), 3.45 (br s, 4H), 3.34 (br s, 4H),3.16-3.12 (m, 2H), 2.85 (s, 3H), 2.18-2.12 (m, 2H).

Example 37

5-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-fluoro-1H-benzoimidazole

HPLC: R_(t)=6.36. MS (electrospray): mass calculated for C₂₁H₂₃Cl₂FN₄O,436.12; m/z found, 437.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.78 (d, J=6.4Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.19 (d, J=2.5Hz, 1H), 7.06 (dd, J=8.8, 2.5 Hz, 1H), 4.14 (t, J=5.8 Hz, 2H), 3.46 (brs, 4H), 3.37 (br s, 3H), 3.22-3.20 (m, 1H), 3.18-3.14 (m, 2H), 2.86 (s,3H), 2.19-2.13 (m, 2H).

Example 38

5-Chloro-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.20. MS (electrospray): mass calculated for C₂₂H₂₇ClN₄O,398.19; m/z found, 399.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.88 (dd,J=8.7, 2.3 Hz, 1H), 7.83-7.82 (m, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.63 (d,J=8.9 Hz, 1H), 7.46 (dd, J=8.7, 1.9 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H),4.16 (t, J=6.0 Hz, 2H), 3.24 (br s, 4H), 2.95 (br s, 4H), 2.88-2.85 (m,2H), 2.77 (s, 3H), 2.26 (s, 3H), 2.11-2.05 (m, 2H).

Example 39

2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-benzoimidazole

HPLC: R_(t)=5.93. MS (electrospray): mass calculated for C₂₂H₂₇ClN₄O,398.19; m/z found, 399.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 8.10 (d, J=2.4Hz, 1H), 7.97 (dd, J=8.7, 2.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.48 (s,1H), 7.34 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 4.24 (t, J=5.8 Hz,2H), 3.34 (br s, 4H), 3.14 (br s, 4H), 3.02-2.99 (m, 2H), 2.80 (s, 3H),2.45 (s, 3H), 2.18-2.12 (m, 2H).

Example 40

5,6-Dichloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.69. MS (electrospray): mass calculated for C₂₁H₂₃Cl₃N₄O,452.09; m/z found, 453.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.08 (d, J=2.3Hz, 1H), 7.95 (dd, J=8.7, 2.3 Hz, 1H), 7.81 (s, 2H), 7.26 (d, J=8.8 Hz,1H), 4.25 (t, J=5.7 Hz, 2H), 3.55 (br s, 8H), 3.36-3.32 (m, 2H), 2.90(s, 3H), 2.31-2.25 (m, 2H).

Example 41

5-Chloro-6-methyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.40. MS (electrospray): mass calculated for C₂₃H₂₉ClN₄O,412.20; m/z found, 413.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.87 (dd,J=8.6, 2.5 Hz, 1H), 7.82-7.81 (m, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.14(d, J=8.7 Hz, 1H), 4.15 (t, J=6.0 Hz, 2H), 3.20 (br s, 4H), 2.85 (br s,4H), 2.83-2.79 (m, 2H), 2.75 (s, 3H), 2.46 (s, 3H), 2.26 (s, 3H),2.08-2.03 (m, 2H).

Example 42

2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-benzoimidazole

HPLC: R_(t)=5.92. MS (electrospray): mass calculated for C₂₂H₂₇ClN₄O,398.19; m/z found, 399.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.87 (d, J=8.8Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.64 (s, 1H), 7.48 (d, J=8.5 Hz, 1H),7.36 (d, J=2.4 Hz, 1H), 7.23 (dd, J=8.8, 2.4 Hz, 1H), 4.26 (t, J=5.8 Hz,2H), 3.60 (br s, 4H), 3.51 (br s, 4H), 3.31-3.27 (m, 2H), 2.98 (s, 3H),2.58 (s, 3H), 2.31-2.26 (m, 2H).

Example 43

5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.15. MS (electrospray): mass calculated for C₂₁H₂₄Cl₂N₄O,418.13; m/z found, 419.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 8.07 (d, J=2.3Hz, 1H), 7.94 (dd, J=8.7, 2.3 Hz, 1H), 7.63 (d, J=1.7 Hz, 1H), 7.59 (d,J=8.7 Hz, 1H), 7.38 (dd, J=8.7, 1.9 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H),4.22 (t, J=5.8 Hz, 2H), 3.42 (br s, 4H), 3.29 (br s. 4H), 3.15-3.10 (m,2H), 2.84 (s, 3H), 2.21-2.15 (m, 2H).

Example 44

2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethyl-1H-benzoimidazole

HPLC: R_(t)=6.53. MS (electrospray): mass calculated for C₂₂H₂₄ClF₃N₄O,452.16; m/z found, 453.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 8.12 (d, J=2.3Hz, 1H), 7.99 (dd, J=8.7, 2.3 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J=8.5 Hz,1H), 7.61 (d, J=8.6 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 4.22 (t, J=5.8 Hz,2H), 3.37 (br s, 4H), 3.21 (br s, 4H), 3.08-3.05 (m, 2H), 2.82 (s, 3H),2.19-2.14 (m, 2H).

Example 45

5-Chloro-6-fluoro-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.34. MS (electrospray): mass calculated for C₂₂H₂₆ClFN₄O,416.18; m/z found, 417.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.85 (dd,J=8.6, 2.3 Hz, 1H), 7.80-7.79 (m, 1H), 7.72 (d, J=6.3 Hz, 1H), 7.51 (d,J=8.6 Hz, 1H), 7.10 (d, J=8.7 Hz, 1H), 4.14 (t, J=6.0 Hz, 2H), 3.20 (brs, 8H), 2.85-2.81 (m, 2H), 2.76 (s, 3H), 2.25 (s, 3H), 2.09-2.04 (m,2H).

Example 46

5-Methyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.13. MS (electrospray): mass calculated for C₂₃H₃₀N₄O,378.24; m/z found, 379.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.87 (d, J=8.6Hz, 1H), 7.82-7.81 (m, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.32(d, J=8.4 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 4.16 (t, J=6.0 Hz, 2H), 3.29(br s, 4H), 3.06 (br s, 4H), 2.96-2.93 (m, 2H), 2.79 (s, 3H), 2.46 (s,3H), 2.26 (s, 3H), 2.14-2.08 (m, 2H).

Example 47

2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=5.70. MS (electrospray): mass calculated for C₂₁H₂₅ClN₄O,384.17; m/z found, 385.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 8.13 (d, J=2.3Hz, 1H), 8.00 (dd, J=8.7, 2.3 Hz, 1H), 7.72-7.67 (m, 2H), 7.53-7.48 (m,2H), 7.33 (d, J=8.8 Hz, 1H), 4.25 (t, J=5.9 Hz, 2H), 3.30 (br s, 4H),3.06 (br s, 4H), 2.96-2.92 (m, 2H), 2.79 (s, 3H), 2.15-2.10 (m, 2H).

Example 48

2-{3-Methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=5.89. MS (electrospray): mass calculated for C₂₂H₂₈N₄O,364.23; m/z found, 365.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.90 (dd,J=8.5, 2.5 Hz, 1H), 7.85-7.84 (m, 1H), 7.70-7.66 (m, 2H), 7.52-7.47 (m,2H), 7.15 (d, J=8.6 Hz, 1H), 4.16 (t, J=6.0 Hz, 2H), 3.23 (br s, 4H),2.96 (br s, 4H), 2.87-2.84 (m, 2H), 2.77 (s, 3H), 2.27 (s, 3H),2.11-2.05 (m, 2H).

Example 49

2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=5.68. MS (electrospray): mass calculated for C₂₁H₂₅ClN₄O,384.17; m/z found, 385.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.78 (d, J=8.8Hz, 1H), 7.77-7.74 (m, 2H), 7.56-7.53 (m, 2H), 7.27 (d, J=2.4 Hz, 1H),7.12 (dd, J=8.8, 2.4 Hz, 1H), 4.16 (t, J=5.9 Hz, 2H), 3.44 (br s, 4H),3.32 (br s, 4H), 3.14-3.11 (m, 2H), 2.84 (s, 3H), 2.18-2.12 (m, 2H).

Example 50

5-Chloro-6-fluoro-2-{3-methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.15. MS (electrospray): mass calculated for C₂₂H₂₆ClFN₄O₂,432.17; m/z found, 433.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.75-7.73 (m,1H), 7.61-7.58 (m, 2H), 7.52 (d, J=8.5 Hz, 1H), 7.09-7.07 (m, 1H), 4.16(t, J=5.6 Hz, 2H), 3.88 (s, 3H), 3.48 (br s, 8H), 3.25-3.22 (m, 2H),2.86 (s, 3H), 2.22-2.19 (m, 2H).

Example 51

2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methoxy-1H-benzoimidazole

HPLC: R_(t)=5.85. MS (electrospray): mass calculated for C₂₂H₂₇ClN₄O₂,414.18; m/z found, 415.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.08 (d, J=2.3Hz, 1H), 7.94 (dd, J=8.7, 2.3 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.30 (d,J=8.8 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 7.10 (dd, J=9.0, 2.3 Hz, 1H),4.26 (t, J=5.7 Hz, 2H), 3.82 (s, 3H), 3.52 (br s, 8H), 3.30-3.26 (m,2H), 2.88 (s, 3H), 2.29-2.22 (m, 2H).

Example 52

5-tert-Butyl-2-{3,5-dibromo-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.81. MS (electrospray): mass calculated for C₂₅H₃₂Br₂N₄O,562.09; m/z found, 563.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 8.31 (s, 2H),7.70-7.62 (m, 3H), 4.17 (t, J=5.8 Hz, 2H), 3.37 (br s, 4H), 3.20 (br s,4H), 3.18-3.15 (m, 2H), 2.82 (s, 3H), 2.22-2.16 (m, 2H), 1.34 (s, 9H).

Example 53

2-{2-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethyl-1H-benzoimidazole

HPLC: R_(t)=6.34. MS (electrospray): mass calculated for C₂₃H₂₇F₃N₄O₂,448.21; m/z found, 449.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 8.11-8.08 (m,2H), 7.96 (d, J=8.6 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 6.89-6.87 (m, 2H),4.28 (t, J=5.8 Hz, 2H), 4.17 (s, 3H), 3.58 (br s, 4H), 3.49 (br s, 4H),3.30-3.27 (m, 2H), 2.97 (s, 3H), 2.31-2.25 (m, 2H).

Example 54

2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethyl-1H-benzoimidazole

HPLC: R_(t)=6.47. MS (electrospray): mass calculated for C₂₂H₂₄ClF₃N₄O,452.16; m/z found, 453.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.09 (s, 1H),7.93 (d, J=8.7 Hz, 1H), 7.85-7.80 (m, 2H), 7.29 (d, J=2.3 Hz, 1H), 7.15(dd, J=8.8, 2.5 Hz, 1H), 4.20 (t, J=5.8 Hz, 2H), 3.62 (br s, 8H),3.40-3.36 (m, 2H), 2.93 (s, 3H), 2.29-2.20 (m, 2H).

Example 55

2-{3-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=5.51. MS (electrospray): mass calculated for C₂₁H₂₆N₄O,350.21; m/z found, 351.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.75-7.72 (m,2H), 7.70-7.60 (m, 2H), 7.54-7.51 (m, 3H), 7.26-7.24 (m, 1H), 4.16 (t,J=6.0 Hz, 2H), 3.35 (br s, 4H), 3.19 (br s, 4H), 3.05-3.01 (m, 2H), 2.81(s, 3H), 2.14-2.10 (m, 2H).

Example 56

(2-{3-[4-(4-Methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimidazol-5-yl)-phenyl-methanone

HPLC: R_(t)=6.36. MS (electrospray): mass calculated for C₂₉H₃₂N₄O₂,468.25; m/z found, 469.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.11 (s, 1H),7.90-7.77 (m, 4H), 7.72-7.65 (m, 3H), 7.58-7.52 (m, 3H), 7.23-7.20 (m,1H), 4.15 (t, J=5.7 Hz, 2H), 3.57 (br s, 8H), 3.26-3.21 (m, 2H), 2.95(s, 3H), 1.96-1.93 (m, 4H).

The following compounds in Examples 57-71 were prepared according to theprocedures described in Example 2.

Example 57

6-Chloro-2-{2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₇Cl₂N₃O, 431.15; m/z found,432.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.69 (d, J=8.0 Hz, 1H), 7.42 (brs, 1H), 7.14 (d, J=4.0 Hz, 1H), 7.07-7.05 (m, 1H), 7.02 (dd, J=8.0, 4.0Hz, 1H), 4.04 (t, J=8.0 Hz, 2H), 2.95-2.85 (m, 2H), 2.58 (s, 3H), 2.28(s, 3H), 2.10-2.00 (m, 2H), 1.84-1.75 (m, 4H), 1.46-1.41 (m, 2H),1.22-1.35 (m, 3H).

Example 58

5-tert-Butyl-2-{3-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₆H₃₄ClN₃O, 439.24; m/z found,440.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.10 (d, J=2.2 Hz, 1H), 7.97 (dd,J=8.6, 2.2 Hz, 1H), 7.58 (br s, 1H), 7.52-7.45 (m, 1H), 7.36 (dd, J=8.6,1.7 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 4.14 (t, J=6.2 Hz, 2H), 2.93-2.85(m, 2H), 2.28 (s, 3H), 2.11-2.00 (m, 2H), 1.92-1.83 (m, 2H), 1.82-1.74(m, 2H), 1.52-1.45 (m, 2H), 1.42-1.20 (m, 12H).

Example 59

2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,5-dimethyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₀ClN₃O, 411.21; m/z found,412.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.73-7.63 (m, 1H), 7.31 (br s,1H), 7.13 (d, J=2.5 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.02 (dd, J=8.7,2.5 Hz, 1H), 4.06 (t, J=6.3 Hz, 2H), 2.93-2.89 (m, 2H), 2.51 (s, 3H),2.40 (s, 3H), 2.29 (s, 3H), 2.00-2.15 (m, 2H), 1.86-1.77 (m, 4H),1.48-1.42 (m, 2H), 1.35-1.24 (m, 3H).

Example 60

5-Chloro-6-methyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.84. MS (electrospray): mass calculated for C₂₃H₂₈ClN₃O,397.19; m/z found, 398.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.95 (d, J=9.0Hz, 2H), 7.67 (s, 1H), 7.57 (s, 1H), 7.12 (d, J=9.0 Hz, 2H), 4.05 (t,J=6.3 Hz, 2H), 3.42 (d, J=10.4 Hz, 2H), 2.92-2.86 (m, 2H), 2.89 (s, 3H),2.45 (s, 3H), 1.96-1.93 (m, 2H), 1.82-1.77 (m, 2H), 1.60-1.52 (m, 1H),1.45-1.30 (m, 4H).

Example 61

5-Chloro-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.62. MS (electrospray): mass calculated for C₂₂H₂₆ClN₃O,383.18; m/z found, 384.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.96 (d, J=9.0Hz, 2H), 7.66 (d, J=2.0 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.42 (dd,J=8.7, 1.9 Hz, 1H), 7.12 (d, J=9.0 Hz, 2H), 4.05 (t, J=6.3 Hz, 2H),3.43-3.40 (m, 2H), 2.92-2.86 (m, 2H), 2.76 (s, 3H), 1.96-1.93 (m, 2H),1.82-1.76 (m, 2H), 1.60-1.51 (m, 1H), 1.46-1.30 (m, 4H).

Example 62

5-Chloro-6-fluoro-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.80. MS (electrospray): mass calculated for C₂₂H₂₅ClFN₃O,401.17; m/z found, 402.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.93 (d, J=9.0Hz, 2H), 7.71 (d, J=6.3 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.08 (d, J=9.0Hz, 2H), 4.03 (t, J=6.3 Hz, 2H), 3.44-3.40 (m, 2H), 2.92-2.86 (m, 2H),2.76 (s, 3H), 1.96-1.93 (m, 2H), 1.82-1.76 (m, 2H), 1.60-1.51 (m, 1H),1.43-1.29 (m, 4H).

Example 63

5-tert-Butyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=7.16. MS (electrospray): mass calculated for C₂₆H₃₅N₃O,405.28; m/z found, 406.6 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 8.09 (d, J=9.0Hz, 2H), 7.70 (s, 1H), 7.71 (s, 2H), 7.25 (d, J=9.0 Hz, 2H), 4.16 (t,J=6.3 Hz, 2H), 3.58-3.52 (m, 2H), 3.03-2.97 (m, 2H), 2.87 (s, 3H),2.06-2.03 (m, 2H), 1.93-1.87 (m, 2H), 1.71-1.63 (m, 1H), 1.57-1.49 (m,4H), 1.44 (s, 9H).

Example 64

5-Methyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.53. MS (electrospray): mass calculated for C₂₃H₂₉N₃O,363.23; m/z found, 364.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.96 (d, J=9.0Hz, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J=8.4 Hz, 1H),7.14 (d, J=9.0 Hz, 2H), 4.05 (t, J=6.2 Hz, 2H), 3.44-3.41 (m, 2H),2.92-2.86 (m, 2H), 2.76 (s, 3H), 2.45 (s, 3H), 1.96-1.92 (m, 2H),1.82-1.76 (m, 2H), 1.60-1.50 (m, 1H), 1.45-1.33 (m, 4H).

Example 65

2-{4-[3-(1-Methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole

HPLC: R_(t)=6.28. MS (electrospray): mass calculated for C₂₂H₂₇N₃O,349.22; m/z found, 350.5 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 8.00 (d, J=8.9Hz, 2H), 7.70-7.66 (m, 2H), 7.51-7.47 (m, 2H), 7.15 (d, J=8.9 Hz, 2H),4.06 (t, J=6.2 Hz, 2H), 3.43-3.40 (m, 2H), 2.92-2.85 (m, 2H), 2.76 (s,3H), 1.96-1.93 (m, 2H), 1.82-1.77 (m, 2H), 1.60-1.50 (m, 1H), 1.45-1.33(m, 4H).

Example 66

6-Chloro-2-{2-fluoro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₇ClFN₃O, 415.18; m/z found,416.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.02 (s, 1H), 7.41 (s, 1H),7.07-7.02 (m, 1H), 6.96-6.85 (m, 2H), 4.06 (t, J=6.3 Hz, 2H), 2.93-2.83(m, 2H), 2.60 (s, 3H), 2.26 (s, 3H), 2.07-1.97 (m, 2H), 1.89-1.71 (m,4H), 1.49-1.40 (m, 2H), 1.38-1.22 (m, 3H).

Example 67

5-Fluoro-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₈FN₃O, 381.22; m/z found,382.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.61-7.52 (m, 2H), 7.29 (dd,J=9.1, 2.3 Hz, 1H), 7.09-7.01 (m, 1H), 6.96-6.86 (m, 2H), 4.04 (t, J=6.4Hz, 2H), 2.95-2.82 (m, 2H), 2.52 (s, 3H), 2.28 (s, 3H), 2.08-1.96 (m,2H), 1.88-1.72 (m, 4H), 1.51-1.40 (m, 2H), 1.38-1.19 (m, 3H).

Example 68

4-Chloro-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₈ClN₃O, 397.19; m/z found,398.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.56 (d, J=8.5 Hz, 1H), 7.54 (d,J=7.7 Hz, 1H), 7.31-7.20 (m, 2H), 6.93 (d, J=2.3 Hz, 1H), 7.90 (dd,J=8.5, 2.5 Hz, 1H), 4.04 (t, J=6.3 Hz, 2H), 2.94-2.84 (m, 2H), 2.51 (s,3H), 2.28 (s, 3H), 2.09-1.97 (m, 2H), 1.89-1.72 (m, 4H), 1.52-1.40 (m,2H), 1.37-1.21 (m, 3H).

Example 69

6-Chloro-4-methyl-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₀ClN₃O, 411.21; m/z found,412.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.54 (d, J=8.4 Hz, 1H), 7.42 (brs, 1H), 7.09-7.05 (m, 1H), 6.94 (d, J=2.3 Hz, 1H), 6.90 (dd, J=8.4, 2.4Hz, 1H), 4.06 (t, J=6.3 Hz, 2H), 2.96-2.86 (m, 2H), 2.59 (s, 3H), 2.49(s, 3H), 2.29 (s, 3H), 2.10-2.00 (m, 2H), 1.90-1.75 (m, 4H), 1.52-1.43(m, 2H), 1.38-1.23 (m, 3H).

Example 70

5-Chloro-2-{2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-6-fluoro-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₄Cl₂FN₃O, 435.13; m/z found,436.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.78 (d, J=8.7 Hz, 1H), 7.70 (d,J=6.6 Hz, 1H), 7.46 (d, J=9.3 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 7.04 (dd,J=8.7, 2.5 Hz, 1H), 4.06 (t, J=6.4 Hz, 2H), 2.93-2.84 (m, 2H), 2.28 (s,3H), 2.09-1.96 (m, 2H), 1.87-1.71 (m, 4H), 1.49-1.39 (m, 2H), 1.35-1.22(m, 3H).

Example 71

2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-3H-naphtho[1,2-d]imidazole

MS (electrospray): mass calculated for C₂₆H₂₈ClN₃O, 433.19; m/z found,434.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.52-8.44 (m, 1H), 7.97 (d, J=8.2Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.74 (s, 2H), 7.64-7.57 (m, 1H),7.53-7.47 (m, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.02 (dd, J=8.6, 2.5 Hz, 1H),4.01 (t, J=6.3 Hz, 2H), 2.89-2.78 (m, 2H), 2.25 (s, 3H), 2.03-1.90 (m,2H), 1.83-1.64 (m, 4H), 1.43-1.33 (m, 2H), 1.33-1.18 (m, 3H).

The following compounds in Examples 72-81 were prepared according to theprocedures described in Example 1.

Example 72

4,6-Dimethyl-2-{2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₂N₄O, 392.26; m/z found,393.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.51 (d, J=8.5 Hz, 1H), 7.20 (s,1H), 6.92-6.70 (m, 3H), 4.07 (t, J=6.1 Hz, 2H), 2.72-2.40 (m, 19H), 2.30(s, 3H), 2.02-1.98 (m, 2H).

Example 73

2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₇ClN₄O, 398.1.9; m/z found,399.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.72-7.67 (m, 1H), 7.41 (s, 1H),7.18-7.13 (m, 2H), 7.07-7.02 (m, 2H), 4.13 (t, J=6.1 Hz, 2H), 2.80-2.40(m, 13H), 2.30 (s, 3H), 2.05-1.98 (m, 2H).

Example 74

2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-fluoro-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₆ClFN₄O, 416.18; m/z found,417.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.76-7.65 (br s, 1H), 7.47-7.33(br s, 1H), 7.17 (d, J=2.5 Hz, 1H), 7.07-7.00 (m, 2H), 4.13 (t, J=6.1Hz, 2H), 2.68-2.40 (m, 13H), 2.32 (s, 3H), 2.08-1.97 (m, 2H).

Example 75

2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-3H-naphtho[1,2-d]imidazole

MS (electrospray): mass calculated for C₂₅H₂₇ClN₄O, 434.19; m/z found,435.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.49 (s, 1H), 7.93 (d, J=8.1 Hz,1H), 7.74-7.68 (m, 3H), 7.60-7.55 (m, 1H), 7.48-7.43 (m, 1H), 7.07 (d,J=2.5 Hz, 1H), 6.90 (dd, J=8.7, 2.5 Hz, 1H), 3.92 (t, J=6.1 Hz, 2H),2.62-2.30 (m, 10H), 2.22 (s, 3H), 1.89-1.81 (m, 2H).

Example 76

6-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazole

MS (electrospray): mass calculated for C₂₂H₂₅ClN₄O₃, 428.16; m/z found,429.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.74 (d, J=8.7 Hz, 1H), 7.13 (d,J=2.5 Hz, 1H), 7.07-6.97 (m, 3H), 5.98 (s, 2H), 4.11 (t, J=6.2 Hz, 2H),2.74-2.36 (m, 10H), 2.31 (s, 3H), 2.07-1.96 (m, 2H).

Example 77

6-Chloro-2-{2-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₈Cl₂N₄O, 446.16; m/z found,447.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.72 (d, J=8.6 Hz, 1H), 7.44 (brs, 1H), 7.18 (d, J=2.5 Hz, 1H), 7.10-7.08 (m, 1H), 7.05 (dd, J=8.7, 2.5Hz, 1H), 4.14 (t, J=6.1 Hz, 2H), 2.83-2.78 (m, 4H), 2.75-2.69 (m, 6H),2.60 (s, 3H), 2.39 (s, 3H), 2.04-1.96 (m, 2H), 1.90-1.84 (m, 2H).

Example 78

2-{3-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₉ClN₄O, 412.20; m/z found,413.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.19 (d, J=2.2 Hz, 1H), 8.04 (dd,J=8.6, 2.2 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H),7.18-7.11 (m, 1H), 7.04 (d, J=7.2 Hz, 1H), 4.19 (t, J=6.0 Hz, 2H),2.84-2.66 (m, 10H), 2.62 (s, 3H), 2.36 (s, 3H), 2.08-1.98 (m, 2H),1.89-1.82 (m, 2H).

Example 79

4,6-Dimethyl-2-{3-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₅H₃₄N₄O, 406.27; m/z found,407.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.75-7.70 (m, 1H), 7.69-7.64 (d,J=7.7 Hz, 1H), 7.46-7.40 (m, 1H), 7.23 (br s, 1H), 7.04 (m, 1H), 6.90(br s, 1H), 4.12 (t, J=6.2 Hz, 2H), 2.83-2.75 (m, 4H), 2.73-2.65 (m,4H), 2.63-2.54 (m, 5H), 2.44 (s, 3H), 2.35 (s, 3H), 1.89-1.79 (m, 4H),1.76-1.68 (m, 2H).

Example 80

5-Chloro-2-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazoleExample 81

2-{4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazoleExample 82

{2-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethyl-amine

A. 4-Bromo-3-dimethylaminomethyl-phenol. 2-Bromo-5-hydroxy-benzaldehyde(5.0 g, 24.9 mmol, 1.0 equiv) and 2.0 M dimethylamine in THF (31 mL, 62mmol, 2.5 equiv) were stirred in dichloroethane (50 mL) at rt for 1.0 h.Sodium triacetoxyborohydride (15.8 g, 75 mmol, 3.0 equiv) was added, andthe mixture was stirred for 3.0 h then poured into satd. aq. NaHCO₃. Theaqueous mixture was extracted three times with chloroform and thecombined extracts were dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified by Method 2 to afford 2.12 g(38%) of the title compound. ¹H NMR (400 MHz, CD₃OD): 7.36 (dd, J=8.6,1.8 Hz, 1H), 6.91-6.90 (m, 1H), 6.67-6.62 (m, 1H), 3.53 (d, J=1.3 Hz,1H), 2.30 (m, 6H).

B.{2-Bromo-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethyl-amine.To a solution of 3-(1-methyl-piperidin-4-yl)-propan-1-ol (989 mg, 6.3mmol, 1.0 equiv) and methanesulfonyl chloride (683 μL, 8.8 mmol, 1.4equiv) in dichloromethane (12 mL) at 0° C. was added triethylamine (1.57mL, 11.3 mmol, 1.8 equiv). The reaction mixture, which was allowed towarm to rt, was stirred for 12 h and then poured into satd. aq. NaHCO₃.The aqueous mixture was extracted three times with 10% 2-propanol inchloroform and the extract was dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was dissolved inacetonitrile (21 mL) and 4-bromo-3-dimethylaminomethyl-phenol (1.44 g,6.3 mmol, 1.0 equiv) and cesium carbonate (4.1 g, 12.6 mmol, 2.0 equiv)were added. The mixture was stirred at rt for 12 h, then warmed to 40°C. for 2.0 h, then 50° C. for 1.0 h, and finally 65° C. for 1.5 h. Themixture was poured into satd. aq. NaHCO₃ and extracted two times withethyl acetate and one time with chloroform. The combined extracts weredried (Na₂SO₄), filtered, and concentrated under reduced pressure.Purification by Method 2 afforded 814 mg (40%) of the title compound. ¹HNMR (400 MHz, CD₃OD): 7.45 (d, J=8.8 Hz, 1H), 7.05 (d, J=3.1 Hz, 1H),6.78 (dd, J=8.8, 3.1 Hz, 1H), 3.98 (t, J=6.4 Hz, 2H), 3.58 (s, 2H),2.93-2.86 (m, 2H), 2.31 (s, 6H), 2.29 (s, 3H), 2.10-1.98 (m, 2H),1.86-1.73 (m, 4H), 1.49-1.22 (m, 5H).

C.{2-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethyl-amine.To a solution of{2-bromo-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethyl-amine(801 mg, 2.2 mmol, 1.0 equiv) in THF (10 mL) at −78° C., 1.7 Mtert-butyllithium in pentane (3.83 mL, 6.5 mmol, 3.0 equiv) was addedand the solution was stirred for 15 min. The solution was then warmed to0° C., stirred for 5 min, and then re-cooled to −78° C. DMF (1.68 mL,21.7 mmol, 10.0 equiv) was added and the mixture was stirred for 30 min.Water (1.0 mL) was added and the mixture was poured into satd. aq.NaHCO₃. The aqueous mixture was extracted three times with ethyl acetateand the combined extracts were dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was partially purifiedby Method 2 to afford 221 mg of a mixture of2-dimethylaminomethyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehydeand several other unidentified products. The crudedimethylaminomethyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde(110 mg) was dissolved in DMF and 5-chloro-3-methyl-benzene-1,2-diamine(54 mg, 0.34 mmol) and Na₂S₂O₅ (85 mg, 0.45 mmol) were added. Themixture was warmed to 90° C. and stirred for 3 h. The reaction mixturewas purified by Method 2 to afford 15.2 mg of the title compound. MS(electrospray): mass calculated for C₂₆H₃₅ClN₄O, 454.25; m/z found,455.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.07 (d, J=8.6 Hz, 1H), 7.47-7.42(m, 1H), 7.07-6.97 (m, 3H), 4.04 (t, J=6.4 Hz, 2H), 3.58 (s, 2H),2.93-2.82 (m, 2H), 2.56 (s, 3H), 2.43 (s, 6H), 2.27 (s, 3H), 2.06-1.93(m, 2H), 1.87-1.70 (m, 4H), 1.49-1.40 (m, 2H), 1.36-1.21 (m, 3H).

Example 83

{2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethyl-amine

The title compound was prepared as described in Example 77. MS(electrospray): mass calculated for C₂₆H₃₅FN₄O, 438.28; m/z found, 439.5[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.06 (d, J=8.6 Hz, 1H), 7.43-7.40 (m,1H), 7.06 (dd, J=8.6, 2.6 Hz, 1H), 7.03-6.95 (m, 2H), 4.06 (t, J=6.4 Hz,2H), 3.59 (s, 2H), 2.89-2.86 (m, 2H), 2.49 (s, 3H), 2.44 (s, 6H), 2.27(s, 3H), 2.07-1.96 (m, 2H), 1.89-1.72 (m, 4H), 1.51-1.41 (m, 2H),1.39-1.22 (m, 3H).

Example 84

4-{3-[4-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-[1,4]diazepan-5-one

A. 4-(3-Iodo-propoxy)-2-methyl-benzaldehyde. 1-Bromo-3-chloropropane(5.03 g, 32.0 mmol, 1.0 equiv) was added to a solution of2-methyl-4-hydroxybenzaldehyde (4.35 g, 32.0 mmol, 1.0 equiv) and K₂CO₃(8.8 g, 64.0 mmol, 2.0 equiv) in acetonitrile (75 mL). The mixture washeated at 65° C. for 16 h, then cooled to rt and filtered throughdiatomaceous earth. The filtrate was concentrated and the residue waspurified by column chromatography (silica gel, 10% ethyl acetate inhexanes) to afford 5.58 g (82%) of4-(3-chloro-propoxy)-2-methyl-benzaldehyde. To a refluxing solution of4-(3-chloro-propoxy)-2-methyl-benzaldehyde in acetone (100 mL), KI (58g) was added portion wise over 3 d. The mixture was cooled to rt andwater was added. The aqueous mixture was extracted three times withethyl acetate and the combined extracts were dried (Na₂SO₄), filtered,and concentrated. The residue was purified by column chromatography(silica gel, 5% ethyl acetate in hexanes) to afford 6.13 g (77%) of thetitle compound. ¹H NMR (400 MHz, CD₃OD): 10.1 (s, 1H), 7.75 (d, J=8.6Hz, 1H), 6.84 (dd, J=8.6, 2.5 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 4.11 (t,J=5.8 Hz, 2H), 3.36 (t, J=6.7 Hz, 2H), 2.65 (s, 3H), 2.29 (m, 2H).

B.4-{3-[4-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-[1,4]diazepan-5-one.To a stirred solution of 5-oxo-[1,4]diazepane-1-carboxylic acidtert-butyl ester (3.0 g, 14.0 mmol, 1.0 equiv) in DMF (45 mL) at rt wasadded 60% sodium hydride (560 mg, 14.0 mmol, 1.0 equiv). After stirringfor 30 min, 4-(3-iodo-propoxy)-2-methyl-benzaldehyde (4.26 g, 14.0 mmol,1.0 equiv) was added as a solution in DMF (5 mL). The mixture wasstirred for 16 h and then poured into water and extracted with ethylacetate. The combined extracts were dried (Na₂SO₄), filtered, andconcentrated. The residue was partially purified by columnchromatography (silica gel, 5-50% ethyl acetate in hexanes) to afford4-[3-(4-formyl-3-methyl-phenoxy)-propyl]-5-oxo-[1,4]diazepane-1-carboxylicacid tert-butyl ester as a mixture with several unidentified products.This impure mixture (200 mg), 5-chloro-3-methyl-benzene-1,2-diamine(80.1 mg), and Na₂S₂O₅ (97 mg) were stirred in DMF (1.0 mL) at 90° C.for 3 h. After cooling to rt, the reaction mixture was loaded on silicagel and was purified by Method 2 to afford4-{3-[4-(6-chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-5-oxo-[1,4]diazepane-1-carboxylicacid tert-butyl ester as a mixture with several unidentified products.This mixture was dissolved in dichloromethane (1.0 mL) and TFA (1.0 mL)and stirred at rt for 1 h. The reaction mixture was loaded on silica geland purified by Method 2 to afford 91.0 mg (42%) of the title compound.MS (electrospray): mass calculated for C₂₃H₂₇ClN₄O₂, 426.18; m/z found,427.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.55 (d, J=8.5 Hz, 1H), 7.42 (brs, 1H), 7.09-7.06 (m, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.93 (dd, J=8.5, 2.5Hz, 1H), 4.10 (t, J=6.1 Hz, 2H), 3.67-3.56 (m, 4H), 2.98-2.89 (m, 4H),2.72-2.66 (m, 2H), 2.59 (s, 3H), 2.50 (s, 3H), 2.12-2.01 (m, 2H).

Example 85

4-{3-[4-(5-tert-Butyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-1-methyl-[1,4]diazepan-5-one

4-{3-[4-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-[1,4]diazepan-5-one(95 mg, 0.22 mmol, 1.0 equiv) and 37% aq. formaldehyde (35 μL, 0.44mmol, 2.0 equiv) were stirred in dichloroethane at rt for 1.0 h. Sodiumtriacetoxyborohydride (139 mg, 0.66 mmol, 3.0 equiv) was added, and themixture was stirred for 1.0 h then poured into satd. aq. NaHCO₃. Theaqueous mixture was extracted three times with ethyl acetate and thecombined extracts were dried (Na₂SO₄), filtered, and concentrated. Theresidue was purified by Method 2 to afford 34 mg (35%) of the titlecompound.

MS (electrospray): mass calculated for C₂₇H₃₆N₄O₂, 448.28; m/z found,449.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.62 (br s, 1H), 7.56 (d, J=8.4Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.38 (dd, J=8.6, 1.7 Hz, 1H), 6.95 (d,J=2.3 Hz, 1H), 6.92 (dd, J=8.5, 2.5 Hz, 1H), 4.09 (t, J=6.0 Hz, 2H),3.65-3.59 (m, 4H), 2.73-2.59 (m, 6H), 2.52 (s, 3H), 2.38 (s, 3H),2.11-2.02 (m, 2H). 1.43 (s, 9H).

Example 86

5-tert-Butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

The title compound was prepared as described in Example 84, substituting3-methyl-piperazine-1-carboxylic acid tert-butyl ester for5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester. MS(electrospray): mass calculated for C₂₆H₃₆N₄O, 420.29; m/z found, 421.5[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.66-7.49 (m, 3H), 7.38 (dd, J=8.6, 1.8Hz, 1H), 6.95 (d, J=2.2 Hz, 1H), 6.91 (dd, J=8.4, 2.5 Hz, 1H), 4.12 (t,J=6.2 Hz, 2H), 3.10-2.82 (m, 5H), 2.60-2.32 (m, 7H), 2.09-1.89 (m, 2H),1.43 (s, 9H), 1.10 (d, J=6.0 Hz, 3H).

Example 87

5-tert-Butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole

The title compound was prepared from5-tert-butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazoleaccording to the method described in Example 85. MS (electrospray): masscalculated for C₂₇H₃₈N₄O, 434.30; m/z found, 435.5 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 7.69-7.47 (m, 3H), 7.38 (dd, J=8.6, 1.9 Hz, 1H), 6.95 (d,J=2.3 Hz, 1H), 6.91 (dd, J=8.5, 2.4 Hz, 1H), 4.11 (t, J=6.2 Hz, 2H),3.10-2.94 (m, 2H), 2.84-2.70 (m, 2H), 2.56-2.39 (m, 6H), 2.31-2.19 (m,4H), 2.09-1.88 (m, 3H), 1.43 (s, 9H), 1.12 (d, J=6.3 Hz, 3H).

Example 88

6-Chloro-4-methyl-2-[2-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-1H-benzoimidazole

To a solution of (3-hydroxy-propyl)-piperidine-1-carboxylic acidtert-butyl ester (4.00 g, 16.4 mmol, 1.0 equiv) and triethylamine (3.40mL, 24.6 mmol, 1.5 equiv) in dichloromethane at 0° C. was addedmethanesulfonyl chloride (1.53 mL, 19.7 mmol, 1.2 equiv). The solutionwas warmed to rt and stirred for 1.0 h then poured into satd. aq.NaHCO₃. The aqueous mixture was extracted three times with chloroformand the combined extracts were dried (Na₂SO₄), filtered, andconcentrated. The residue was subjected to column chromatography (silicagel, 10% methanol in dichloromethane). The partially purified4-(3-methanesulfonyloxy-propyl)-piperidine-1-carboxylic acid tert-butylester (500 mg, 1.56 mmol, 1.0 equiv) was stirred with4-hydroxy-2-methyl-benzaldehyde (212 mg, 1.56 mmol, 1.0 equiv) andcesium carbonate (1.01 g, 3.12 mmol, 2.0 equiv) in acetonitrile at rtfor 4 d. The mixture was filtered through diatomaceous earth and thefiltrate was concentrated. The crude material was partially purified bycolumn chromatography (silica gel, 25% ethyl acetate in hexanes).4-[3-(4-Formyl-3-methyl-phenoxy)-propyl]-piperidine-1-carboxylic acidtert-butyl ester (146 mg, 0.41 mmol, 1.0 equiv),5-chloro-3-methyl-benzene-1,2-diamine (63 mg, 0.41 mmol, 1.0 equiv), andNa₂S₂O₅ (100 mg, 0.53 mmol, 1.3 equiv) were stirred at 90° C. in DMF for2.5 h. The mixture was cooled to rt and water (75 mL) was added causinga light brown precipitate to form. The solid4-{3-[4-(6-chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-piperidine-1-carboxylicacid tert-butyl ester was collected by filtration, dissolved in asolution of dichloromethane (2.0 mL) and trifluoroacetic acid (1.0 mL),and stirred at rt for 1.5 h. The reaction mixture was loaded directly onsilica gel and purified according to Method 2, which afforded 52.1 mg ofthe title compound. MS (electrospray): mass calculated for C₂₃H₂₈ClN₃O,397.19; m/z found, 398.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.55 (d, J=8.4Hz, 1H), 7.42 (br s, 1H), 7.10-7.07 (m, 1H), 6.96-6.95 (m, 1H), 6.91(dd, J=8.5, 2.4 Hz, 1H), 4.09 (t, J=6.2 Hz, 2H), 3.45-3.39 (m, 2H),3.06-2.96 (m, 2H), 2.59 (s, 3H), 2.50 (s, 3H), 2.07-1.99 (m, 2H),1.93-1.84 (m, 2H), 1.76-1.64 (m, 1H), 1.59-1.50 (m, 2H), 1.48-1.36 (m,2H).

Example 89

5-Fluoro-4-methyl-2-[2-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-1H-benzoimidazole

The title compound was prepared as described in Example 88. MS(electrospray): mass calculated for C₂₃H₂₈FN₃O, 381.22; m/z found, 382.4[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.56 (d, J=8.5 Hz, 1H), 7.44-7.38 (m,1H), 7.09-7.02 (m, 1H), 6.96 (d, J=2.3 Hz, 1H), 6.91 (dd, J=8.4, 2.5 Hz,1H), 4.09 (t, J=6.2 Hz, 2H), 3.44-3.36 (m, 2H), 3.06-2.95 (m, 2H), 2.52(d, J=1.6 Hz, 3H), 2.50 (s, 3H), 2.08-1.98 (m, 2H), 1.94-1.83 (m, 2H),1.77-1.65 (m, 1H), 1.59-1.50 (m, 2H), 1.48-1.35 (m, 2H).

Example 90

6-Chloro-2-{4-[3-(1-ethyl-piperidin-4-yl)-propoxy]-2-methyl-phenyl}-4-methyl-1H-benzoimidazole

The title compound was prepared as described in Example 85, substitutingacetaldehyde for aq. formaldehyde. MS (electrospray): mass calculatedfor C₂₅H₃₂ClN₃O, 425.22; m/z found, 426.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): 7.53 (d, J=8.5 Hz, 1H), 7.41 (br s, 1H), 7.09-7.04 (m, 1H), 6.93(d, J=2.2 Hz, 1H), 6.89 (dd, J=8.4, 2.4 Hz, 1H), 4.04 (t, J=6.3 Hz, 2H),3.05-2.94 (m, 2H), 2.59 (s, 3H), 2.49 (s, 3H), 2.45 (q, J=7.2 Hz, 2H),2.05-1.94 (m, 2H), 1.89-1.74 (m, 4H), 1.50-1.21 (m, 5H), 1.13 (t, J=7.2Hz, 3H).

Example 91

{2-[3-Chloro-4-(4-methyl-1H-benzoimidazol-2-yl)-phenoxy]-ethyl}-methyl-(1-methyl-piperidin-4-yl)-amine

A. 4-(2-Bromo-ethoxy)-2-chloro-benzaldehyde. 1,2-Dibromoethane (5.5 mL,64.0 mmol, 5.0 equiv) was added to a mixture of2-chloro-4-hydroxy-benzaldehyde (2.0 g, 12.8 mmol, 1.0 equiv) and K₂CO₃(4.0 g, 29.0 mmol, 2.25 equiv) in acetonitrile (13 mL). The mixture washeated at reflux for 16 h, cooled to rt, and filtered throughdiatomaceous earth. The filtrate was concentrated to yield crudeproduct, which was purified by column chromatography (silica gel, 5%ethyl acetate in hexanes) to afford 2.28 g (72%) of the title compound.¹H NMR (400 MHz, CD₃OD): 10.3 (d, J=0.7 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H),7.13 (d, J=2.4 Hz, 1H), 7.06 (ddd, J=8.8, 2.5, 0.7 Hz, 1H), 4.48-4.42(m, 2H), 3.78-3.74 (m, 2H).

B.2-Chloro-4-{(2-[methyl-(1-methyl-piperidin-4-yl)-amino]-ethoxy}-benzaldehyde.To a solution of 4-(2-bromo-ethoxy)-2-chloro-benzaldehyde (1.24 g, 5.0mmol, 1.0 equiv) and methyl-(1-methyl-piperidin-4-yl)-amine (1.28 g,10.0 mmol, 2.0 equiv) in 1-butanol was added K₂CO₃ (2.10 g, 15 mmol, 3.0equiv) and the solution was warmed to 90° C. After stirring for 16 h,the mixture was poured into water and extracted two times with ethylacetate. The combined extracts were dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by Method 2 to afford 467 mg(30%) of the title compound.

¹H NMR (400 MHz, CD₃OD): 10.3 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.13 (d,J=2.4 Hz, 1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 4.21 (t, J=5.5 Hz, 2H),3.00-2.88 (m, 4H), 2.57-2.47 (m, 1H), 2.41 (s, 3H), 2.29 (s, 3H),2.11-2.01 (m, 2H), 1.91-1.82 (m, 2H), 1.68-1.58 (m, 2H).

C.{2-[3-Chloro-4-(4-methyl-1H-benzoimidazol-2-yl)-phenoxy]-ethyl}-methyl-(1-methyl-piperidin-4-yl)-amine.This compound was prepared by the method described in General Procedure3 using2-chloro-4-{2-[methyl-(1-methyl-piperidin-4-yl)-amino]-ethoxy}-benzaldehyde(62.2 mg, 0.20 mmol, 1.0 equiv), 3-methyl-benzene-1,2-diamine (26 mg,0.20 mmol, 1.0 equiv), and Na₂S₂O₅ (50 mg, 0.26 mmol, 1.3 equiv).Purification by Method 2 afforded 29 mg (35%) of the title compound. MS(electrospray): mass calculated for C₂₃H₂₉ClN₄O, 412.20; m/z found,413.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.73 (d, J=8.6 Hz, 1H), 7.49-7.40(m, 1H), 7.22-7.14 (m, 2H), 7.11-7.04 (m, 2H), 4.18 (t, J=5.5 Hz, 2H),3.00-2.92 (m, 4H), 2.62 (s, 3H), 2.56-2.48 (m, 1H), 2.41 (s, 3H), 2.28(s, 3H), 2.11-1.99 (m, 2H), 1.92-1.81 (m, 2H), 1.70-1.55 (m, 2H).

Example 92

6-Chloro-4-methyl-2-{2-methyl-4-[2-(1-methyl-piperidin-4-yloxy)-ethoxy]-phenyl}-1H-benzoimidazole

A. 4-[2-(4-Formyl-3-methyl-phenoxy)-ethoxy]-1-methyl-piperidiniumtoluene-4-sulfonate. To a solution of 1,4-dioxa-8-aza-spiro[4.5]decane(1.0 g, 7.0 mmol, 1.0 equiv) in toluene (20 mL) at 0° C. was added 1.0 Mdiisobutylaluminum hydride in hexane (20 mL, 20 mmol, 2.9 equiv). Thesolution was warmed to 80° C. and stirred for 12 h. Methanol (20 mL),satd. aq. sodium potassium tartrate (20 mL), and 10% 2-propanol inchloroform (100 mL) were added and the mixture was stirred for 30 min.The chloroform layer was separated and the aqueous mixture was extractedfive times with 10% 2-propanol in chloroform (25 mL). The combinedextracts were dried (Na₂SO₄), filtered, and concentrated to providecrude 2-(piperidin-4-yloxy)-ethanol as a white solid. The solid wasdissolved in dichloroethane (20 mL) and 37% aq. formaldehyde (0.60 mL,6.9 mmol) was added. After stirring for 30 min, sodiumtriacetoxyborohydride (2.04 g, 9.6 mmol) was added and the mixture wasstirred for 1.5 h. The reaction mixture was diluted with satd. aq.NaHCO₃ (20 mL) and extracted six times with 10% 2-propanol in chloroform(80 mL). The combined extracts were dried (Na₂SO₄), filtered, andconcentrated to give 2-(1-methyl-piperidin-4-yloxy)-ethanol. The residuewas dissolved in dichloromethane, cooled to 0° C., and pyridine (463 μL,5.7 mmol) and p-toluenesulfonyl chloride (1.1 g, 5.7 mmol) were added.The solution was warmed to rt and stirred for 16 h. The reaction mixturewas concentrated under reduced pressure and the residue was partiallypurified by Method 2. The resulting material, toluene-4-sulfonic acid2-(1-methyl-piperidin-4-yloxy)-ethyl ester, was added to a mixture of4-hydroxy-2-methyl-benzaldehyde (275 mg, 2.0 mmol) and K₂CO₃ (699 mg,5.1 mmol) in DMF. The mixture was heated to 100° C. and stirred for 16h. After cooling to rt, the mixture was poured into water and extractedthree times with ethyl acetate. The combined extracts were dried(Na₂SO₄), filtered, and concentrated. The crude product was purified byMethod 2 to afford 409 mg of the title compound. ¹H NMR (400 MHz,CD₃OD): 10.10 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.2 Hz, 2H),7.26 (d, J=7.9 Hz, 2H), 6.96 (dd, J=8.6, 2.4 Hz, 1H), 6.88 (d, J=2.1 Hz,1H), 4.27-4.22 (m, 2H), 3.90-3.85 (m, 2H), 3.75-3.65 (m, 1H), 3.19-3.07(m, 2H), 3.03-2.86 (m, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 2.39 (s, 3H),2.07-1.83 (m, 4H).

B.6-Chloro-4-methyl-2-{2-methyl-4-[2-(1-methyl-piperidin-4-yloxy)-ethoxy]-phenyl}-1H-benzoimidazole.This compound was prepared by the method described in General Procedure3 using 4-[2-(4-formyl-3-methyl-phenoxy)-ethoxy]-1-methyl-piperidiniumtoluene-4-sulfonate (47.5 mg, 0.11 mmol, 1.0 equiv),5-chloro-3-methyl-benzene-1,2-diamine (27 mg, 0.17 mmol, 1.6 equiv), andNa₂S₂O₅ (42 mg, 0.22 mmol, 2.1 equiv). Purification by Method 2 afforded20 mg (46%) of the title compound. MS (electrospray): mass calculatedfor C₂₃H₂₈ClN₃O₂, 413.19; m/z found, 414.3 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): 7.55 (d, J=8.5 Hz, 1H), 7.42 (br s, 1H), 7.08-7.05 (m, 1H), 6.98(d, J=2.3 Hz, 1H), 6.93 (dd, J=8.5, 2.5 Hz, 1H), 4.21-4.17 (m, 2H),3.88-3.83 (m, 2H), 3.57-3.47 (m, 1H), 2.81-2.67 (m, 2H), 2.59 (s, 3H),2.50 (s, 3H), 2.33-2.20 (m, 5H), 2.02-1.90 (m, 2H), 1.76-1.60 (m, 2H).

Example 93

6-Chloro-4-methyl-2-{2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole

A. 3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propan-1-ol. To asolution of 4-(3-hydroxy-propyl)-1-methyl-pyridinium iodide (28 g, 100.4mmol, 1.0 equiv) in ethanol (200 mL) at 0° C. was added sodiumborohydride (5.7 g, 151 mmol, 1.5 equiv). The reaction mixture, whichwas allowed to warm to rt, was stirred for 30 min and then poured intowater. The aqueous solution was extracted with ethyl acetate and theextract was dried (Na₂SO₄), filtered, and concentrated to afford 15.2 g(97%) of the title compound. ¹H NMR (400 MHz, CD₃OD): 5.46-5.41 (m, 1H),3.56 (t, J=6.6 Hz, 2H), 2.98-2.91 (m, 2H), 2.60 (t, J=5.9 Hz, 2H), 2.35(s, 3H), 2.21-2.14 (m, 2H), 2.12-2.04 (m, 2H), 1.71-1.62 (m, 2H).

B.2-Methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-benzaldehyde.To a solution of3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propan-1-ol (2.24 g, 14.5mmol, 1.0 equiv) and pyridine (1.64 mL, 20.2 mmol, 1.4 equiv) indichloromethane (50 mL) at 0° C. was added p-toluenesulfonyl chloride(3.85 g, 20.2 mmol, 1.4 equiv). The reaction mixture, which was allowedto warm to rt, was stirred for 12 h and then poured into water. Theaqueous mixture was extracted with dichloromethane and the extract wasdried (Na₂SO₄), filtered, and concentrated. The residue was subjected tocolumn chromatography on silica gel (10% methanol in dichloromethane)and the resulting oil was added to a mixture of4-hydroxy-2-methyl-benzaldehyde (639 mg, 4.69 mmol) and K₂CO₃ (1.62 g,11.7 mmol) in DMF and warmed to 100° C. After stirring for 16 h, themixture was allowed to cool to rt and filtered through a pad ofdiatomaceous earth. The diatomaceous earth was rinsed with ethylacetate, and the filtrate was concentrated. The residue was purified byMethod 2 to afford 356 mg (9%) of the title compound. ¹H NMR (400 MHz,CD₃OD): 10.1 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 6.92 (dd, J=8.6, 2.4 Hz,1H), 6.84 (d, J=2.1 Hz, 1H), 5.49-5.43 (m, 1H), 4.09 (t, J=6.3 Hz, 2H),2.97-2.91 (m, 2H), 2.65-2.57 (m, 5H), 2.35 (s, 3H), 2.25-2.16 (m, 4H),1.99-1.88 (m, 2H).

C.6-Chloro-4-methyl-2-{2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole.This compound was prepared by the method described in General Procedure3 using2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-benzaldehyde(50 mg, 0.18 mmol, 1.0 equiv), 5-chloro-3-methyl-benzene-1,2-diamine (29mg, 0.18 mmol, 1.0 equiv), and Na₂S₂O₅ (45.2 mg, 0.24 mmol, 1.3 equiv).Purification by Method 2 afforded 15.7 mg (21%) of the title compound.MS (electrospray): mass calculated for C₂₄H₂₈ClN₃O, 409.19; m/z found,410.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.53 (d, J=8.5 Hz, 1H), 7.41 (brs, 1H), 7.08-7.04 (m, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.89 (dd, J=8.5, 2.5Hz, 1H), 5.49-5.44 (m, 1H), 4.04 (t, J=6.3 Hz, 2H), 2.96-2.91 (m, 2H),2.64-2.56 (m, 5H), 2.49 (s, 3H), 2.35 (s, 3H), 2.28-2.16 (m, 4H),1.96-1.88 (m, 2H).

Example 94

5-Fluoro-4-methyl-2-{2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole

The title compound was prepared as described in Example 93. MS(electrospray): mass calculated for C₂₄H₂₈FN₃O, 393.22; m/z found, 394.4[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.54 (d, J=8.5 Hz, 1H), 7.39 (br s,1H), 7.05-6.95 (m, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.5, 2.5 Hz,1H), 5.50-5.46 (m, 1H), 4.06 (t, J=6.3 Hz, 2H), 2.99-2.94 (m, 2H),2.65-2.59 (m, 2H), 2.53-2.47 (m, 6H), 2.36 (s, 3H), 2.27-2.18 (m, 4H),1.98-1.90 (m, 2H).

Example 95

6-Fluoro-7-methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole

A. 3-[4-(1-Methyl-piperidin-4-yl)-butoxy]-benzonitrile.4-(1-Methyl-piperidin-4-yl)-butan-1-ol (0.747 g, 4.37 mmol, 1.0 equiv),3-hydroxy-benzonitrile (0.52 g, 4.37 mmol, 1.0 equiv), andpolymer-supported triphenylphosphine (2.3 g, 8.73 mmol, 2.0 equiv) weresuspended in THF (40 mL). The mixture was stirred under N₂ and cooled to0° C. Diisopropyl azodicarboxylate (1.72 mL, 8.73 mmol, 2.0 equiv) wasadded dropwise via syringe. After 6 h, the mixture was filtered andconcentrated. The resulting crude oil was purified by Method 2 to afford0.84 g (71%) of the title compound. MS (electrospray): mass calculatedfor C₁₇H₂₄N₂O, 272.19; m/z found, 273.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.38-7.33 (m, 1H), 7.24-7.20 (m, 1H), 7.14-7.09 (m, 2H), 3.96 (t, J=6.4Hz, 2H), 2.88-2.80 (m, 2H), 2.26 (s, 3H), 1.94-1.84 (m, 2H), 1.82-1.73(m, 2H), 1.72-1.64 (m, 2H), 1.52-1.42 (m, 2H), 1.34-1.17 (m, 5H).

B. 3-[4-(1-Methyl-piperidin-4-yl)-butoxy]-benzaldehyde. To a stirredsolution of 3-[4-(1-methyl-piperidin-4-yl)-butoxy]-benzonitrile (0.84 g,3.09 mmol, 1.0 equiv) in toluene (5.0 mL) at 0° C. was added 1.5 Mdiisobutylaluminum hydride in toluene (4.63 mL, 4.63 mmol, 1.5 equiv).After 3 h, methanol (9.0 mL) and 1.0 M H₂SO₄ (10 mL) were addeddropwise. After stirring for 30 min, 1.0 M NaOH (10 mL) was added,followed by satd. aq. sodium potassium tartrate (40 mL) anddichloromethane (100 mL). The solution was extracted three times withchloroform (50 mL) and the combined extracts were washed with brine,dried (Na₂SO₄), filtered, and concentrated. The crude oil was purifiedby Method 2 to afford 0.56 g (66%) of the title compound. ¹H NMR (400MHz, CDCl₃): 9.97 (s, 1H), 7.46-7.43 (m, 2H), 7.39-7.37 (m, 1H),7.19-7.15 (m, 1H), 4.02 (t, J=6.6 Hz, 2H), 2.86-2.80 (m, 2H), 2.25 (s,3H), 1.92-1.83 (m, 2H), 1.83-1.75 (m, 2H), 1.73-1.63 (m, 2H), 1.54-1.44(m, 2H), 1.34-1.18 (m, 5H).

C.6-Fluoro-7-methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole.This compound was prepared by the method described in General Procedure3 using 3-[4-(1-methyl-piperidin-4-yl)-butoxy]-benzaldehyde (20 mg, 0.07mmol, 1.0 equiv), 4-fluoro-3-methyl-benzene-1,2-diamine (12 mg, 0.09mmol, 1.0 equiv) and Na₂S₂O₅ (18 mg, 0.10 mmol, 1.3 equiv). Purificationby Method 2 afforded 28.7 mg (54%) of the title compound. MS(electrospray): mass calculated for C₂₄H₃₀FN₃O, 395.24; m/z found, 396.4[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.72-7.62 (m, 2H), 7.47-7.32 (m, 2H),7.08-6.94 (m, 2H), 4.07 (t, J=6.3 Hz, 2H), 2.90-2.80 (m, 2H), 2.53 (s,3H), 2.24 (s, 3H), 2.04-1.92 (m, 2H), 1.85-1.66 (m, 4H), 1.59-1.47 (m,2H), 1.39-1.17 (m, 5H).

The following compounds in Examples 96-101 were prepared according tothe procedures described in Example 95.

Example 96

7-Methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₁N₃O, 377.25; m/z found,378.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.86-7.71 (m, 2H), 7.44 (br s,1H), 7.29-7.22 (m, 1H), 7.26-7.09 (m, 1H), 7.02 (d, J=7.3 Hz, 1H), 6.89(dd, J=8.2, 1.8 Hz, 1H), 3.59 (t, J=6.4 Hz, 2H), 2.82 (m, 2H), 2.52 (brs, 3H), 2.25 (s, 3H), 1.89 (m, 2H), 1.63-1.47 (m, 4H), 1.28-1.07 (m,7H).

Example 97

6,7-Dimethyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₅H₃₃N₃O, 391.56; m/z found,392.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.73-7.61 (m, 2H), 7.46-7.36 (m,1H), 7.36-7.25 (m, 1H), 7.09-6.98 (m, 2H), 4.08 (t, J=6.3 Hz, 2H),2.93-2.82 (m, 2H), 2.53 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H), 2.08-1.97(m, 2H), 1.86-1.68 (m, 4H), 1.60-1.47 (m, 2H), 1.39-1.17 (m, 5H).

Example 98

5-Chloro-7-methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₀ClN₃O, 411.21; m/z found,412.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.73-7.62 (m, 2H), 7.47-7.38 (m,2H), 7.09-7.02 (m, 2H), 4.09 (t, J=6.3 Hz, 2H), 2.91-2.81 (m, 2H), 2.68(s, 3H), 2.24 (s, 3H), 2.05-1.93 (m, 2H), 1.87-1.67 (m, 4H), 1.60-1.48(m, 2H), 1.39-1.18 (m, 5H).

Example 99

5,7-Dimethyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₆H₃₅N₃O, 405.28; m/z found,406.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.30-7.23 (m, 1H), 7.19 (s, 1H),7.16-7.11 (m, 1H), 7.07-7.01 (m, 1H), 6.89 (s, 1H), 4.04 (t, J=6.4 Hz,2H), 2.89-2.80 (m, 2H), 2.54 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.23(s, 3H), 2.04-1.91 (m, 2H), 1.88-1.77 (m, 2H), 1.77-1.68 (m, 2H),1.61-1.49 (m, 2H), 1.40-1.17 (m, 5H).

Example 100

5-Chloro-7-methyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₅H₃₂ClN₃O, 425.22; m/z found,426.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.40 (s, 1H), 7.33-7.24 (m, 1H),7.17-7.10 (m, 1H), 7.10-7.02 (m, 2H), 4.04 (t, J=5.6 Hz, 2H), 2.91-2.80(m, 2H), 2.56 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 2.04-1.92 (m, 2H),1.89-1.65 (m, 4H), 1.63-1.48 (m, 2H), 1.41-1.16 (m, 5H).

Example 101

6-Fluoro-7-methyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₅H₃₂FN₃O, 409.25; m/z found,410.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.43-7.33 (s, 1H), 7.30 (t, J=7.8Hz, 1H), 7.16-7.10 (s, 1H), 7.10-6.96 (m, 2H), 4.05 (t, J=5.4 Hz, 2H),2.91-2.81 (m, 2H), 2.49 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H), 2.07-1.94(m, 2H), 1.89-1.67 (m, 4H), 1.63-1.49 (m, 2H), 1.41-1.16 (m, 5H).

Example 102

6-Fluoro-7-methyl-2-{3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-phenyl}-1H-benzoimidazole

A. 3-[3-(1-Methyl-piperidin-4-yloxy)-propoxy]-benzonitrile. To a mixtureof 3-(1-methyl-piperidin-4-yloxy)-propan-1-ol (295 mg, 1.7 mmol, 1.0equiv) and polymer-supported triphenylphosphine (1.14 g, 3.41 mmol, 2.0equiv) in THF (40 mL) at 0° C. was added diisopropyl azodicarboxylate(0.67 mL, 3.41 mmol, 2.0 equiv) dropwise via syringe. After 6 h, themixture was filtered through a glass frit and the filtrate wasconcentrated. The crude oil was purified by Method 2 to afford 187 mg(40%) of the title compound. MS (electrospray): mass calculated forC₁₆H₂₂N₂O₂, 274.17; m/z found, 275.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.40-7.33 (m, 1H), 7.25-7.21 (m, 1H), 7.17-7.10 (m, 2H), 4.09 (t, J=6.2Hz, 2H), 3.61 (t, J=6.2 Hz, 2H), 3.34-3.25 (m, 1H), 2.73-2.61 (m, 2H),2.26 (s, 3H), 2.17-2.00 (m, 4H), 1.94-1.84 (m, 2H), 1.68-1.55 (m, 2H).

B.6-Fluoro-7-methyl-2-{3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-phenyl}-1H-benzoimidazole.To a stirred solution of3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzonitrile (0187 g, 0.68mmol, 1.0 equiv) in toluene (5.0 mL) at 0° C. was added 1.5 Mdiisobutylaluminum hydride in toluene (1.02 mL, 1.02 mmol, 1.5 equiv).After 3 h, methanol (9 mL) and 1 M H₂SO₄ (10 mL) were added. The mixturewas stirred for 30 min, then 1.0 M NaOH (10 mL) was added, followed bysatd. aq. sodium potassium tartrate (40 mL) and dichloromethane (100mL). After stirring for 30 min, the mixture was extracted three timeswith chloroform (50 mL) and the combined extracts were washed withbrine, dried (Na₂SO₄), filtered, and concentrated. The residue waspartially purified by Method 2 to afford 106 mg of a mixture of3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde and severalother unidentified products. A solution of the crude3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde (53 mg),4-fluoro-3-methyl-benzene-1,2-diamine (27 mg), and Na₂S₂O₅ in DMF wasstirred at 90° C. for 18 h. The reaction mixture was loaded directly onsilica gel and purified according to Method 2, which afforded 28.7 mg ofthe title compound.

MS (electrospray): mass calculated for C₂₃H₂₈FN₃O₂, 397.22; m/z found,398.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.64-7.53 (m, 2H), 7.38-7.25 (m,2H), 7.00-6.85 (m, 2H), 4.06 (t, J=6.1 Hz, 2H), 3.60-3.52 (m, 2H),3.33-3.19 (br s, 1H), 2.58 (br s, 2H), 2.42 (s, 3H), 2.17-2.03 (m, 5H),2.01-1.90 (m, 2H), 1.86-1.72 (m, 2H), 1.60-1.42 (m, 2H).

Example 103

6-Chloro-4-methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

A. 6-[3-(4-Methyl-piperazin-1-yl)-propoxy]-nicotinonitrile. To a stirredsolution of 3-(4-methyl-piperazin-1-yl)-propan-1-ol (1.0 g, 6.32 mmol,1.0 equiv) in DMF (60 mL) under an atmosphere of nitrogen, was added 60%sodium hydride (379 mg, 9.48 mmol, 1.5 equiv) portion wise. Once theinitial effervescence had subsided, the mixture was heated at 60° C. for1 h then cooled to rt. A solution of 6-chloronicotinonitrile (876 mg,6.32 mmol, 1.0 equiv) in DMF (5 mL) was then added and the mixturestirred for 16 h. The reaction mixture was partitioned between satd. aq.NaHCO₃ (30 mL) and chloroform (60 mL). The organic layer was dried(Na₂SO₄), filtered, and concentrated to give a crude mixture, which waspurified by column chromatography (silica gel, 0-10% (2.0 M ammonia inmethanol) in dichloromethane) to afford 776 mg (47%) of a beige solid.MS (electrospray): mass calculated for C₁₄H₂₀N₄O, 260.16; m/z found,261.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.47 (dd, J=2.3, 0.8 Hz, 1H),7.77 (dd, J=8.6, 2.3 Hz, 1H), 6.80 (dd, J=8.6, 0.8 Hz, 1H), 4.41 (t,J=6.6 Hz, 2H), 2.76-2.35 (m, 10H), 2.29 (s, 3H), 2.01-1.95 (m, 2H).

B. 6-[3-(4-Methyl-piperazin-1-yl)-propoxy]-pyridine-3-carbaldehyde. To acooled (0° C.) solution of6-[3-(4-methyl-piperazin-1-yl)-propoxy]-nicotinonitrile (486 mg, 1.86mmol, 1.0 equiv) in toluene (20 mL), under an atmosphere of nitrogen,was added 1 M diisobutylaluminum hydride in hexanes (2.79 mL, 2.79 mmol,1.5 equiv) dropwise. The mixture was warmed to rt and stirred for 2 h.Methanol was added (5 mL), followed by 1 M H₂SO₄ (10 mL). After stirringfor 30 min, the solution was neutralized with satd. aq. NaHCO₃, dilutedwith satd. aq. sodium potassium tartrate (10 mL), and stirred anadditional 30 min or until clear. The mixture was extracted withchloroform (3×50 mL) and the combined extracts were dried (Na₂SO₄), andconcentrated, yielding the crude product, which was purified by columnchromatography (silica gel, 0-10% (2 M ammonia in methanol) indichloromethane) to afford 225 mg (46%) of a colorless residue. MS(electrospray): mass calculated for C₁₄H₂₁N₃O₂, 263.16; m/z found, 264.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): ¹H NMR (400 MHz, CDCl₃): 9.94 (1H, s),8.61 (d, J=2.3 Hz, 1H), 8.06 (dd, J=8.6, 2.3 Hz, 1H), 6.82 (d, J=8.6 Hz,1H), 4.46 (t, J=6.6 Hz, 2H), 2.64-2.33 (m, 10H), 2.29 (s, 3H), 2.03-1.96(m, 2H).

C.6-Chloro-4-methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole.This compound was prepared by the method described in General Procedure3 using 6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridine-3-carbaldehyde(49 mg, 0.17 mmol, 1.0 equiv), 5-chloro-3-methyl-benzene-1,2-diamine (27mg, 0.17 mmol, 1.0 equiv), and Na₂S₂O₅ (42 mg, 0.22 mmol, 1.3 equiv).Purification by Method 2 afforded 54 mg (79%) of the title compound.

MS (electrospray): mass calculated for C₂₁H₂₆ClN₅O, 399.18; m/z found,400.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.75 (s, 1H), 8.25 (dd, J=8.2,2.4 Hz, 1H), 7.49-7.32 (m, 1H), 6.91 (s, 1H), 6.71 (d, J=8.7 Hz, 1H),4.28 (t, J=6.7 Hz, 2H), 2.67-2.31 (m, 13H), 2.26 (s, 3H), 1.98-1.87 (m,2H).

The following compounds in Examples 104-105 were prepared according tothe procedures described in Example 103.

Example 104

4-Methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₁H₂₇N₅O, 365.47; m/z found,366.2 [M+H]⁺.

Example 105

5-Fluoro-4-methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₁H₂₆FN₅O, 383.46; m/z found,384.2 [M+H]⁺.

Example 106

4-Methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

A. 6-[3-(1-Methyl-Piperidin-4-yl)-propoxy]-nicotinonitrile. To a stirredsolution of 3-(1-methyl-piperidin-4-yl)-propan-1-ol (5.0 g, 31.7 mmol,1.1 equiv) in DMF (200 mL) under an atmosphere of nitrogen, was added60% sodium hydride (1.73 g, 43.3 mmol, 1.5 equiv) portion wise. Once theinitial effervescence had subsided, the mixture was heated at 60° C. for1 h then cooled to rt. A solution of 6-chloronicotinonitrile (4.0 g,28.9 mmol, 1.0 equiv) in DMF (20 mL) was then added and the mixturestirred for 16 h. The reaction was quenched with satd. aq. NaHCO₃ (50mL) and brine (50 mL). A precipitate was formed and was collected byvacuum filtration to afford 3.67 g of the desired product. The filtratewas concentrated to half the volume and a second crop of precipitate wascollected and combined to give 5.64 g (76%) of an orange solid, whichwas used without further purification. MS (electrospray): masscalculated for C₁₅H₂₁N₃O, 259.17; m/z found, 260.4 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.46 (dd, J=2.3, 0.8 Hz, 1H), 7.77 (dd, J=8.6, 2.3 Hz, 1H),6.80 (dd, J=8.6, 0.8 Hz, 1H), 4.34 (t, J=6.6 Hz, 2H), 2.96-2.82 (m, 2H),2.25 (s, 3H), 1.92-1.68 (m, 7H), 1.37-1.34 (m, 2H), 0.89-0.81 (m, 2H).

B. 6-[3-(1-Methyl-Piperidin-4-yl)-propoxy]-pyridine-3-carbaldehyde. To acooled (0° C.) solution of6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (640 mg, 2.47mmol, 1.0 equiv) in toluene (20 mL), under an atmosphere of nitrogen,was added 1 M diisobutylaluminum hydride in hexanes (3.70 mL, 3.70 mmol,1.5 equiv) dropwise. The mixture was warmed to rt and stirred for 2 h.Methanol was added (5 mL), followed by 1 M H₂SO₄ (10 mL). After stirringfor 30 min the solution was neutralized with satd. aq. NaHCO₃, dilutedwith satd. aq. sodium potassium tartrate (10 mL), and stirred anadditional 30 min or until clear. The mixture was extracted withchloroform (3×50 mL) and the combined extracts were dried (Na₂SO₄),filtered and concentrated. The crude product was purified by columnchromatography (silica gel, 0-10% (2 M ammonia in methanol) indichloromethane) to afford 598 mg (92%) of a colorless oil. MS(electrospray): mass calculated for C₁₅H₂₂N₂O₂, 262.17; m/z found, 263.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): ¹H NMR (400 MHz, CDCl₃): 9.87 (br s,1H), 8.53 (d, J=2.3 Hz, 1H), 7.98 (dd, J=8.6, 2.3 Hz, 1H), 6.74 (d,J=8.6 Hz, 1H), 4.34 (t, J=6.6 Hz, 2H), 2.78-2.26 (m, 2H), 2.19 (s, 3H),1.85-1.62 (m, 7H), 1.35-1.16 (m, 4H).

C.4-Methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole.This compound was prepared by the method described in General Procedure3 using 6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-3-carbaldehyde(100 mg, 0.38 mmol, 1.0 equiv), 3-methyl-benzene-1,2-diamine (46 mg,0.38 mmol, 1.0 equiv) and Na₂S₂O₅ (94 mg, 0.50 mmol, 1.3 equiv).Purification by Method 2 afforded 35 mg (25%) of the title compound. MS(electrospray): mass calculated for C₂₂H₂₈N₄O, 364.23; m/z found, 365.4[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.77 (s, 1H), 8.23 (dd, J=8.7, 2.3 Hz,1H), 7.25 (m, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.04-6.98 (m, 1H), 6.74 (d,J=8.7 Hz, 1H), 4.34 (t, J=6.6 Hz, 2H), 2.84-2.76 (m, 2H), 2.73-2.34 (brs, 3H), 2.23 (s, 3H), 1.92-1.83 (m, 2H), 1.81-1.62 (m, 4H), 1.39-1.17(m, 5H).

The following compounds in Examples 107-108 were prepared according tothe procedures described in Example 106.

Example 107

4,5-Dimethyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₃₀N₄O, 378.24; m/z found,379.4 [M+H]⁺.

Example 108

4-Chloro-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₁H₂₅ClN₄O, 384.17; m/z found,385.3 [M+H]⁺.

Example 109

6-Chloro-4-methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

A. 4-Methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile. Toa stirred solution of 2,2,6,6-tetramethyl-piperidine (0.20 mL, 1.16mmol, 1.5 equiv) in THF (3 mL) at −78° C. was added 2.5 M n-butyllithiumin hexanes (0.46 mL, 1.16 mmol, 1.5 equiv). After 10 min, the reactionmixture was warmed to 0° C. for 45 min before re-cooling to −78° C. Asolution of 6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (200mg, 0.77 mmol, 1.0 equiv) in THF (3 mL) was then added. After stirringfor 1 h at −78° C., the mixture was treated with methyl iodide (0.05 mL,0.84 mmol, 1.1 equiv) and stirring was continued for 1.5 h beforequenching at −78° C. with satd. aq. NaHCO₃ (5 mL). The mixture waswarmed to rt and extracted with chloroform (2×10 mL). The combinedextracts were dried (Na₂SO₄), filtered, and concentrated to give a cruderesidue, which was purified by Method 2 to give 120 mg (57%) of thetitle compound. MS (electrospray): mass calculated for C₁₆H₂₃N₃O,273.18; m/z found, 274.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.39 (s, 1H),6.67 (s, 1H), 4.31 (t, J=6.7 Hz, 2H), 2.90-2.79 (m, 2H), 2.48 (s, 3H),2.28 (s, 3H), 1.95-1.63 (m, 6H), 1.40-1.20 (m, 5H).

B.4-Methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-3-Carbaldehyde.To a solution of4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (260mg, 0.95 mmol, 1.0 equiv) in toluene (10 mL) at 0° C. was added 1.5 Mdiisobutylaluminum hydride in toluene (1.26 mL, 1.90 mmol, 2.0 equiv).The mixture was warmed to rt and stirred for 2 h. Methanol (2 mL) wasadded, followed by 1.0 M H₂SO₄ (3 mL). After stirring for 30 min, thesolution was neutralized with satd. aq. NaHCO₃, diluted with satd. aq.sodium potassium tartrate (10 mL), and stirred an additional 30 min oruntil clear. The mixture was extracted with chloroform (3×15 mL) and thecombined extracts were dried (Na₂SO₄), filtered, and concentrated toafford 200 mg of the crude product, which was used without purification.¹H NMR (400 MHz, CDCl₃): 10.0 (s, 1H), 8.47 (s, 1H), 6.57 (s, 1H), 4.35(t, J=6.7 Hz, 2H), 2.86-2.80 (m, 2H), 2.59 (s, 3H), 2.25 (s, 3H),1.92-1.66 (m, 6H), 1.43-1.22 (m, 5H).

C.4-Methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole.This compound was prepared by the method described in General Procedure3 using4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-3-carbaldehyde(60 mg, 0.22 mmol, 1.0 equiv), 5-chloro-3-methyl-benzene-1,2-diamine (34mg, 0.22 mmol, 1.0 equiv) and Na₂S₂O₅ (54 mg, 0.29 mmol, 1.3 equiv).Purification by Method 2 afforded 27 mg (30%) of the title compound. MS(electrospray): mass calculated for C₂₃H₂₉ClN₄O, 412.20; m/z found,413.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.77 (s, 1H), 8.23 (dd, J=8.7,2.3 Hz, 1H), 7.25 (m, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.04-6.98 (m, 1H),6.74 (d, J=8.7 Hz, 1H), 4.34 (t, J=6.6 Hz, 2H), 2.84-2.76 (m, 2H),2.73-2.34 (br s, 3H), 2.23 (s, 3H), 1.92-1.83 (m, 2H), 1.81-1.62 (m,4H), 1.39-1.17 (m, 4H).

The following compounds in Examples 110-114 were prepared according tothe procedures described in Example 109.

Example 110

4-Methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₃₀N₄O, 378.24; m/z found,379.5 [M+H]⁺.

Example 111

5-Fluoro-4-methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₉FN₄O, 396.23; m/z found,397.4 [M+H]⁺.

Example 112

4,5-Dimethyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₂N₄O, 392.26; m/z found,393.5 [M+H]⁺.

Example 113

4,6-Dimethyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₂N₄O, 392.26; m/z found,393.5 [M+H]⁺.

Example 114

4-Chloro-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₇ClN₄O, 398.19; m/z found,399.3 [M+H]⁺.

Example 115

2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-5-fluoro-4-methyl-1H-benzoimidazole

A. 4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile. Toa stirred solution of 2,2,6,6-tetramethyl-piperidine (0.31 mL, 2.32mmol, 1.2 equiv) in THF (10 mL) at −78° C. was added 1.6 Mn-butyllithium in hexanes (1.45 mL, 2.32 mmol, 1.2 equiv). After 10 minthe reaction mixture was warmed to 0° C. for 45 min before re-cooling to−78° C. A solution of6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (500 mg, 1.93mmol, 1.0 equiv) in THF (10 mL) was then added. After stirring for 1 hat −78° C., the mixture was treated with hexachloroethane (0.05 mL, 0.84mmol, 1.1 equiv) in THF (2 mL) and allowed to warm to 0° C. Stirring wascontinued for 1.5 h before quenching at 0° C. with sodium hydrogencarbonate (10 mL). The mixture was warmed to rt and extracted withchloroform (2×20 mL). The combined extracts were dried (Na₂SO₄),filtered, and concentrated to give a crude residue, which was purifiedby Method 2 to give 380 mg (67%) of the title compound. MS(electrospray): mass calculated for C₁₅H₂₀ClN₃O, 293.13; m/z found,294.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.43 (s, 1H), 6.87 (s, 1H), 4.35(t, J=6.7 Hz, 2H), 2.97-2.88 (m, 2H), 2.33 (s, 3H), 2.05-1.94 (m, 2H),1.83-1.67 (m, 5H), 1.43-1.23 (m, 4H).

B.2-[4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl]-5-fluoro-4-methyl-1H-benzoimidazole.To a solution of4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (380mg, 1.30 mmol, 1.0 equiv) in toluene (10 mL) at 0° C. was added 1.5 Mdiisobutylaluminum hydride in toluene (1.72 mL, 2.60 mmol, 2.0 equiv).The mixture was warmed to rt and stirred for 2 h. Methanol was added (5mL), followed by 1.0 M H₂SO₄ (5 mL). After stirring for 30 min, thesolution was neutralized with satd. aq. NaHCO₃, diluted with satd. aq.sodium potassium tartrate (10 mL), and stirred an additional 30 min oruntil clear. The mixture was extracted with chloroform (3×15 mL) and thecombined extracts were dried (Na₂SO₄), filtered, and concentrated toafford 132 mg of the crude product which was used without purification.This crude mixture (33 mg, 0.11 mmol, 1.0 equiv) was used as describedin General Procedure 3 with 4-fluoro-3-methyl-benzene-1,2-diamine (16mg, 0.11 mmol, 1.0 equiv) and Na₂S₂O₅ (27 mg, 0.14 mmol, 1.3 equiv).Purification by Method 2 afforded 12 mg (26%) of an oily residue. MS(electrospray): mass calculated for C₂₂H₂₆ClFN₄O, 416.18; m/z found,417.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.48 (s, 1H), 7.41 (dd, J=8.7,4.3 Hz, 1H), 7.46-6.99 (m, 2H), 4.36 (t, J=6.6 Hz, 2H), 2.91-2.82 (m,2H), 2.50 (s, 3H), 2.25 (s, 3H), 2.06-1.95 (m, 2H), 1.88-1.69 (m, 4H),1.47-1.18 (m, 5H).

The following compounds in Examples 116-118 were prepared according tothe procedures described in Example 115.

Example 116

2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₇ClN₄O, 398.19; m/z found,399.3. [M+H]⁺.

Example 117

6-Chloro-2-{4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₆Cl₂N₄O, 432.15; m/z found,433.3 [M+H]⁺.

Example 118

2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4,6-dimethyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₉ClN₄O, 412.20; m/z found,413.4 [M+H]⁺.

Example 119

2-{4-Methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methyl-1H-benzoimidazole

A solution of4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile(Example 115) in methanol (0.2 M) was treated with sodium methoxide (4equiv) at reflux temperature for 4 h. The mixture was cooled to rt,diluted with satd. aq. NaHCO₃, and extracted with chloroform. Theorganic extract was dried (Na₂SO₄), filtered, and concentrated to yield4-methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile(100%). This intermediate was converted to the title compound accordingto Example 115. MS (electrospray): mass calculated for C₂₃H₃₀ClN₄O₂,394.24; m/z found, 395.4 [M+H]⁺.

Example 120

5-Fluoro-2-{4-methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methyl-1H-benzoimidazole

The title compound was prepared according to the procedures described inExample 119. MS (electrospray): mass calculated for C₂₃H₂₉FN₄O₂, 412.23;m/z found, 413.4 [M+H]⁺.

Example 121

5-Fluoro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

A.6-[3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-nicotinonitrile.To a stirred solution of3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propan-1-ol (1.23 g, 7.94mmol, 1.1 equiv) in DMF (50 mL), under an atmosphere of nitrogen, wasadded 60% sodium hydride (433 mg, 10.8 mmol, 1.5 equiv) portion wise.Once the initial effervescence had subsided, the mixture was heated at60° C. for 1 h then cooled to rt. A solution of 6-chloronicotinonitrile(1.0 g, 7.21 mmol, 1.0 equiv) in DMF (5 mL) was then added and themixture was stirred for 16 h. The reaction was quenched with satd. aq.NaHCO₃ (10 mL) and brine (10 mL). The mixture was extracted withchloroform (2×50 mL). The combined extracts were dried (Na₂SO₄),filtered, and concentrated to give a crude residue, which was purifiedby Method 2 affording 1.43 g (77%) of the title compound. MS(electrospray): mass calculated for C₁₅H₁₉N₃O, 257.15; m/z found, 258.3[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.46 (dd, J=2.4, 0.6 Hz, 1H), 7.76 (dd,J=8.7, 2.4 Hz, 1H), 6.80 (dd, J=8.7, 0.6 Hz, 1H), 5.44-5.39 (m, 1H),4.35 (t, J=6.6 Hz, 2H), 2.92-2.87 (m, 2H), 2.51 (t, J=5.8 Hz, 2H), 2.34(s, 3H), 2.18-2.08 (m, 4H), 1.96-1.83 (m, 2H).

B.6-[3-(1-Methyl-1,2,3,6-tetrahydro-Pyridin-4-yl)-propoxy]-pyridine-3-carbaldehyde.To a cooled (0° C.) solution of6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-nicotinonitrile(1.42 mg, 5.56 mmol, 1.0 equiv) in toluene (40 mL), under an atmosphereof nitrogen, was added 1.0 M diisobutylaluminum hydride in hexanes (8.34mL, 8.34 mmol, 1.5 equiv). dropwise. The mixture was warmed to rt andstirred for 2 h. Methanol was added (5 mL), followed by 1.0 M H₂SO₄ (10mL). After stirring for 30 min, the solution was neutralized with satd.aq. NaHCO₃, diluted with satd. aq. sodium potassium tartrate (25 mL),and stirred an additional 30 min or until clear. The mixture wasextracted with chloroform (3×50 mL) and the combined extracts were dried(Na₂SO₄), filtered, and concentrated to afford 1.29 g of the productwhich was used without purification. ¹H NMR (400 MHz, CDCl₃): 9.93 (s,1H), 8.60 (d, J=2.3 Hz, 1H), 8.05 (dd, J=8.7, 2.3 Hz, 1H), 6.81 (d,J=8.7 Hz, 1H), 5.45-5.39 (m, 1H), 4.40 (t, J=6.6 Hz, 2H), 2.92-2.86 (m,2H), 2.54-2.48 (m, 2H), 2.30 (s, 3H), 2.18-2.09 (m, 4H), 2.98-1.84 (m,2H).

C.5-Fluoro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-Propoxy]-pyridin-3-yl}-1H-benzoimidazole.This compound was prepared by the method described in General Procedure3 using6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridine-3-carbaldehyde(100 mg, 0.39 mmol, 1.0 equiv), 4-fluoro-3-methyl-benzene-1,2-diamine(66 mg, 0.39 mmol, 1.0 equiv) and Na₂S₂O₅ (96 mg, 0.51 mmol, 1.3 equiv).Purification by Method 2 afforded 24 mg (16%) of the title compound. MS(electrospray): mass calculated for C₂₂H₂₅FN₄O, 380.20; m/z found, 381.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 11.8-10.8 (br s, 1H), 8.86-8.58 (m,1H), 8.24 (dd, J=8.7, 2.5 Hz, 1H), 7.58-7.36 (m, 0.5H), 7.21-7.03 (m,0.5H), 6.93 (t, J=9.9 Hz, 1H), 6.73 (d, J=8.7 Hz, 1H), 5.42-5.33 (m,1H), 4.29 (t, J=6.7 Hz, 2H), 2.92-2.81 (m, 2H), 2.58-2.44 (m, 4H),2.36-2.26 (m, 4H), 2.18-2.02 (m, 4H), 1.93-1.82 (m, 2H).

The following compounds in Examples 122-126 were prepared according tothe procedures described in Example 121.

Example 122

4-Methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₆N₄O, 362.21; m/z found,363.4 [M+H]⁺.

Example 123

6-Chloro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₅ClN₄O, 396.17; m/z found,397.4 [M+H]⁺.

Example 124

4,5-Dimethyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₈N₄O, 376.23; m/z found,377.4 [M+H]⁺.

Example 125

4,6-Dimethyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₈N₄O, 376.23; m/z found,377.4 [M+H]⁺.

Example 126

5-Chloro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₅ClN₄O, 396.17; m/z found,397.4 [M+H]⁺.

Example 127

5-Fluoro-4-methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-4-pyrrolidin-1-ylmethyl-pyridin-3-yl}-1H-benzoimidazole

A. 5-Bromo-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine. To astirred solution of 3-(1-methyl-piperidin-4-yl)-propan-1-ol (2.0 g, 12.7mmol, 1.0 equiv), in DMF (100 mL) under an atmosphere of nitrogen, wasadded 60% sodium hydride (764 mg, 19.1 mmol, 1.5 equiv) portion wise.Once the initial effervescence had subsided, the mixture was heated at60° C. for 1 h, then was cooled to rt. A solution of 2,5-dibromopyridine(3.0 g, 12.7 mmol, 1.0 equiv) in DMF (7 mL) was then added and themixture was stirred for 16 h. The reaction was quenched with satd. aq.NaHCO₃ (25 mL) and brine (25 mL). The mixture was extracted withchloroform (2×30 mL). The organic extracts were dried (Na₂SO₄),filtered, and concentrated to give a crude residue, which was purifiedby Method 2 affording 3.31 g (88%) of the title compound. ¹H NMR (400MHz, CDCl₃): 8.18-8.13 (m, 1H), 7.65-7.58 (m, 1H), 6.65-6.60 (m, 1H),4.21 (t, J=6.7 Hz, 2H), 2.87-2.80 (m, 2H), 2.26 (s, 3H), 1.94-1.62 (m,6H), 1.43-1.17 (m, 5H).

B.5-Bromo-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-4-carbaldehyde.To a cooled solution (−78° C.) of 2.0 M LDA in heptane/THF (4.05 mL,8.07 mmol, 2.0 equiv) in THF (20 mL), was added a solution of5-bromo-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine (1.2 g, 3.85mmol, 1.0 equiv) in THF (15 mL) dropwise. After 30 min, DMF (1.49 mL,19.2 mmol, 5.0 equiv) was added dropwise and the mixture stirred for anadditional 20 min at −78° C. then warmed to 0° C. and quenched withsatd. aq. NaHCO₃ (5 mL). The mixture was warmed to rt and extracted withchloroform (2×30 mL). The combined extracts were dried (Na₂SO₄),filtered, and concentrated to afford 1.10 g of a crude oil, which wasused without purification. ¹H NMR (400 MHz, CDCl₃): 10.3 (s, 1H), 8.39(s, 1H), 7.15 (s, 1H), 4.31 (t, J=6.7 Hz, 2H), 2.87-2.75 (m, 2H), 2.28(s, 3H), 1.97-1.60 (m, 6H), 1.43-1.15 (m, 5H).

C.5-Bromo-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-4-pyrrolidin-1-ylmethyl-pyridine.To a mixture of5-bromo-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-4-carbaldehyde(85 mg, 0.25 mmol, 1.0 equiv) and pyrrolidine (0.05 mL, 0.62 mmol, 2.5equiv) in dichloroethane (5 mL), was added sodium triacetoxyborohydride(156 mg, 0.74 mmol, 3.0 equiv). After 24 h, the mixture was neutralizedwith satd. aq. NaHCO₃ and extracted with chloroform (2×15 mL). Thecombined extracts were dried (Na₂SO₄), filtered, and concentrated togive a crude oil product, which was purified by Method 2 to give 38 mgof a white solid. ¹H NMR (400 MHz, CDCl₃): 8.15 (s, 1H), 6.90 (s, 1H),4.24 (t, J=6.7 Hz, 2H), 3.65 (s, 2H), 2.87-2.77 (m, 2H), 2.64-2.53 (m,4H), 2.25 (s, 3H), 1.95-1.62 (m, 10H), 1.42-1.20 (m, 5H).

D.5-Fluoro-4-methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-4-pyrrolidin-1-ylmethyl-pyridin-3-yl}-1H-benzoimidazole.To a cooled solution (−78° C.) of5-bromo-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-4-pyrrolidin-1-ylmethyl-pyridine(38 mg, 0.10 mmol, 1.0 equiv) in dry THF (2 mL), under an atmosphere ofnitrogen, was added n-butyllithium (2.75 M in hexanes, 0.04 mL, 0.11mmol, 1.1 equiv) dropwise. After 10 min, DMF (0.07 mL, 1.00 mmol, 10.0equiv) was added. The solution was warmed to 0° C., quenched with satd.aq. NaHCO₃ (2 mL), and extracted with chloroform (2×10 mL). The combinedextracts were dried (Na₂SO₄), filtered, and concentrated to obtain acrude residue. This residue was immediately dissolved in DMF (2 mL) andtreated with 4-fluoro-4-fluoro-3-methyl-benzene-1,2-diamine (15 mg, 0.11mmol, 1.1 equiv) and Na₂S₂O₅ (25 mg, 0.13 mmol, 1.3 equiv) according toGeneral Procedure 3. Purification by Method 2 afforded 10 mg (22%) ofthe title compound. MS (electrospray): mass calculated for C₂₇H₃₆FN₅O,465.26; m/z found, 466.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.81 (s, 1H),7.42 (dd, J=8.7, 4.3 Hz, 1H), 7.01 (dd, J=10.3, 8.8 Hz, 1H), 6.95 (s,1H), 4.40 (t, J=6.6 Hz, 2H), 3.79 (s, 3H), 2.94-2.81 (m, 2H), 2.77-2.66(m, 4H), 2.51 (s, 3H), 2.25 (s, 3H), 2.00-1.92 (m, 6H), 1.89-1.70 (m,4H), 1.46-1.19 (m, 5H).

Example 128

2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole

A. 5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-Pyridine. To a stirredsolution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (3.98 g, 623 mmol,1.1 equiv) in DMF (100 mL), under an atmosphere of nitrogen, was added60% sodium hydride (1.26 mg, 6.81 mmol, 1.5 equiv) portion wise. Oncethe initial effervescence had subsided, the mixture was heated at 60° C.for 1 h, then was cooled to rt. A solution of 2,5-dibromopyridine (5 mg,21.1 mmol, 1.0 equiv) in DMF (50 mL) was then added and the mixture wasstirred for 16 h. The mixture was partitioned between satd. aq. NaHCO₃(100 mL) and chloroform (200 mL). The chloroform layer was dried(Na₂SO₄), filtered, and concentrated to give a crude mixture, which waspurified by column chromatography (silica gel, 0-10% (2 M ammonia inmethanol) in dichloromethane) to afford 2.73 g (40%) of a white solid.MS (electrospray): mass calculated for C₁₅H₂₃BrN₂O, 326.1; m/z found,327.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.17 (d, J=2.5 Hz, 1H), 7.63 (dd,J=7.6, 2.5 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 4.24 (t, J=6.6 Hz, 2H),2.91-2.80 (m, 2H), 2.27 (s, 3H), 1.98-1.88 (m, 2H), 1.79-1.63 (m, 4H),1.49-1.38 (m, 2H), 1.34-1.20 (m, 5H).

B.5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-Pyridine-4-carbaldehyde.To a cooled solution (−78° C.) of 2.0 M LDA in heptane/THF (3.47 mL,6.94 mmol, 2.0 equiv) in THF (10 ML), was added a solution of5-bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine (1.13 g, 3.47mmol, 1.0 equiv) in THF (15 mL) dropwise. After 30 min, DMF (1.07 mL,13.9 mmol, 4.0 equiv) was added dropwise and the mixture stirred for anadditional 20 min at −78° C. The mixture was warmed to 0° C. and satd.aq. NaHCO₃ (5 mL) was added. After warming to rt, the mixture wasextracted with chloroform (2×20 mL). The combined extracts were dried(Na₂SO₄), filtered, and concentrated to give 1.34 g of a crude orangeoil which was used without purification. ¹H NMR (400 MHz, CDCl₃): 10.3(s, 1H), 8.39 (s, 1H), 7.14 (s, 1H), 4.31 (t, J=6.7 Hz, 2H), 2.89-2.79(m, 2H), 2.28 (s, 3H), 1.96-1.63 (m, 9H), 1.43-1.20 (m, 4H).

C.2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole.This compound was prepared by the method described in General Procedure3 using5-bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbaldehyde(100 mg, 0.28 mmol, 1.0 equiv), 3-methyl-benzene-1,2-diamine (38 mg,0.31 mmol, 1.1 equiv) and Na₂S₂O₅ (70 mg, 0.37 mmol, 1.3 equiv).Purification by Method 2 afforded 25 mg (20%) of the title compound.

MS (electrospray): mass calculated for C₂₃H₂₉BrN₄O, 456.15; m/z found,466.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 10.6-10.3 (br s, 1H), 8.45-8.28(m, 1H), 7.76-7.62 (m, 2H), 7.25-7.21 (m, 1H), 7.19-7.07 (m, 1H), 4.29(t, J=6.7 Hz, 2H), 2.87-2.77 (m, 2H), 2.76-2.63 (m, 3H), 2.25 (s, 3H),1.95-1.61 (m, 7H), 1.53-1.39 (m, 2H), 1.35-1.15 (m, 4H).

The following compounds in Examples 129-135 were prepared according tothe procedures described in Example 128.

Example 129

2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₈BrFN₅O, 474.14; m/z found,477.4 [M+H]⁺.

Example 130

2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-6-chloro-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₈BrClN₅O, 490.1; m/z found,493.4 [M+H]⁺.

Example 131

2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimethyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₁BrN₄O, 470.17; m/z found,471.4 [M+H]⁺.

Example 132

2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₁BrN₄O, 470.17; m/z found,471.4 [M+H]⁺.

Example 133

2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₁BrN₄O, 470.17 m/z found,471.4 [M+H]⁺. MS (electrospray): mass calculated for C₂₃H₂₈BrClN₄O,490.11; m/z found, 493.4 [M+H]⁺.

Example 134

2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-tert-butyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₆H₃₅BrN₄O, 498.20; m/z found,501.4 [M+H]⁺.

Example 135

5-tert-Butyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₆H₃₆N₄O, 420.29; m/z found,421.5 [M+H]⁺.

Example 136

2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole

A. 5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine. To astirred solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (1.5 g, 8.77mmol, 1.0 equiv) in DMF (10 mL) under an atmosphere of nitrogen, wasadded 60% sodium hydride (573 mg, 14.3 mmol, 1.5 equiv) portion wise.Once the initial effervescence had subsided, the mixture was heated at60° C. for 1 h, then was cooled to rt. A solution of2,5-dichloropyridine (1.42 mg, 9.55 mmol, 1.1 equiv) in DMF (10 mL) wasthen added and the mixture was stirred for 4 h. The mixture waspartitioned between satd. aq. NaHCO₃ (20 mL) and chloroform (40 mL). Thechloroform layer was dried (Na₂SO₄), filtered, and concentrated to givea crude mixture, which was purified by column chromatography (silicagel, 0-10% (2 M ammonia in methanol) in dichloromethane) to afford 1.62g (65%) of a white solid. ¹H NMR (400 MHz, CDCl₃): 8.07 (dd, J=2.5, 0.4Hz, 1H), 7.51 (dd, J=8.8, 2.7 Hz, 1H), 6.67 (dd, J=8.8, 0.4 Hz, 1H),4.27 (t, J=6.6 Hz, 2H), 2.86-2.78 (m, 2H), 2.26 (s, 3H), 1.94-1.60 (m,7H), 1.52-1.37 (m, 2H), 1.35-1.14 (m, 4H).

B.5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbaldehyde.To a cooled solution (−78° C.) of 2.0 M LDA in heptane/THF (5.74 mL,11.5 mmol, 2.0 equiv) in THF (10 ML), was added a solution of5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine (1.62 g, 5.74mmol, 1.0 equiv) in THF (15 mL) dropwise. After 30 min, DMF (2.22 mL,28.7 mmol, 5.0 equiv) was added dropwise and the mixture was stirred foran additional 20 min at −78° C. The mixture was warmed to 0° C. andquenched with satd. aq. NaHCO₃ (5 mL). The mixture was warmed to rt andextracted with chloroform (2×20 mL). The combined extracts were dried(Na₂SO₄), filtered, and concentrated to give 968 mg of a crude residue,which was used without purification. ¹H NMR (400 MHz, CDCl₃): 10.4 (s,1H), 8.26 (s, 1H), 7.13 (s, 1H), 4.31 (t, J=6.6 Hz, 2H), 2.87-2.80 (m,2H), 2.25 (s, 3H), 1.99-1.60 (m, 7H), 1.51-1.38 (m, 2H), 1.43-1.20 (m,4H).

C.2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole.This compound was prepared by the method described in General Procedure3 using5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbaldehyde(45 mg, 0.15 mmol, 1.0 equiv), 4-fluoro-3-methyl-benzene-1,2-diamine (23mg, 0.17 mmol, 1.1 equiv) and Na₂S₂O₅ (37 mg, 0.20 mmol, 1.3 equiv).Purification by Method 2 afforded 12 mg (18%) of the title compound. MS(electrospray): mass calculated for C₂₃H₂₈ClFN₄O, 430.19; m/z found,431.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.30 (s, 1H), 7.45 (dd, J=8.9,4.5 Hz, 1H), 7.22-7.19 (m, 1H), 7.07 (dd, J=10.2, 8.9 Hz 1H), 4.31 (t,J=6.6 Hz, 2H), 2.88-2.81 (m, 2H), 2.53 (s, 3H), 2.24 (s, 3H), 2.05-1.90(m, 2H), 1.84-1.66 (m, 4H), 1.55-1.42 (m, 2H), 1.37-1.15 (m, 5H).

Example 137

2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole

The title compound was prepared according to the methods described inExample 136. MS (electrospray): mass calculated for C₂₄H₃₁ClN₄O, 426.22;m/z found, 427.4 [M+H]⁺.

Example 138

4,6-Dimethyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

A. 2-[4-(4-Methyl-piperazin-1-yl)-butoxy]-isonicotinonitrile. To asolution of 4-(4-methyl-piperazin-1-yl)-butan-1-ol (2.5 g, 14.5 mmol,1.0 equiv) in DMF (25 mL) at 0° C. was added sodium hydride (60%dispersion in oil, 0.70 g, 17.4 mmol, 1.2 equiv). The mixture was warmedto rt and stirred for 1 h before re-cooling to 0° C. A solution of2-chloro-isonicotinonitrile (2.01 g, 14.5 mmol, 1.0 equiv) in DMF (12mL) was added dropwise. The mixture was stirred at rt for 18 h. Thereaction was diluted with water (5 mL) and satd. aq. NaHCO₃ (25 mL) wasadded. The mixture was extracted with chloroform (3×25 mL), and thecombined extracts were concentrated. Purification by Method 2 afforded1.07 g of impure compound. Mass calculated for C₁₅H₂₂N₄O, 274.18; m/zfound, 275.4 [M+H]⁺.

B.4,6-Dimethyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-Pyridin-4-yl}-1H-benzoimidazole.To a stirred solution of2-[4-(4-methyl-piperazin-1-yl)-butoxy]-isonicotinonitrile) in toluene(5.0 mL) at 0° C. was added 1.5 M diisobutylaluminum hydride in toluene(3.9 mL, 5.86 mmol, 1.5 equiv). After 3 h, methanol (9 mL) and 1.0 MH₂SO₄ (10 mL) were added. The mixture was stirred for 30 min, and then1.0 M NaOH (10 mL) was added, followed by satd. aq. sodium potassiumtartrate (40 mL) and dichloromethane (100 mL). After stirring for 30min, the mixture was extracted with chloroform (3×50 mL) and thecombined extracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated. The residue was partially purified by Method 2 to afford240 mg of a mixture of3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde and severalother unidentified products. A portion of the crude3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde (40 mg),3,5-dimethyl-benzene-1,2-diamine (17.6 mg), and Na₂S₂O₅ (32 mg) werestirred in DMF (4 mL) at 90° C. for 18 h. The reaction mixture wasloaded directly on silica gel and purified by Method 2, which afforded19 mg of the title compound. MS (electrospray): mass calculated forC₂₃H₃₁N₅O, 393.25; m/z found, 394.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):8.26 (d, J=5.4 Hz, 1H), 7.63 (d, J=5.5 Hz, 1H), 7.49 (s, 1H), 7.25 (brs, 1H), 6.95 (s, 1H), 4.38 (t, J=6.3 Hz, 2H), 2.76-2.33 (m, 16H),2.32-2.24 (s, 3H), 1.92-1.79 (m, 2H), 1.79-1.66 (m, 2H).

The following compounds in Examples 139-142 were prepared according tothe procedures described in Example 138.

Example 139

4-Methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₉N₅O, 379.24; m/z found,380.4 [M+H]⁺.

Example 140

4,5-Dimethyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₃₁N₅O, 393.25; m/z found,394.5 [M+H]⁺.

Example 141

5-Fluoro-4-methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₈FN₅O, 397.23; m/z found,398.4 [M+H]⁺.

Example 142

6-Chloro-4-methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₈ClN₅O, 413.20; m/z found,414.4 [M+H]⁺.

Example 143

5-Fluoro-4-methyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

A. 2-[4-(4-Methyl-[1,4]diazepan-1-yl)-butoxy]-isonicotinonitrile. To asolution of 1-methyl-[1,4]diazepane (21.3 g, 185 mmol, 2.0 equiv) and4-chloro-butan-1-ol (10.0 g, 92.6 mmol, 1.0 equiv) in 1-butanol (200 mL)were added K₂CO₃ (38.0 g, 278 mmol, 3.0 equiv) and NaI (13.9 g, 92.6mmol, 1.0 equiv). The mixture was warmed to 95° C. and stirred for 36 h.The mixture was then cooled to rt, diluted with water, and extractedwith chloroform (3×100 mL). The combined extracts were washed withbrine, dried (MgSO₄), filtered, and concentrated. Purification by Method2 afforded 9.3 g of 4-(4-methyl-[1,4]diazepan-1-yl)-butan-1-ol with asmall unidentified impurity. A portion of the impure alcohol (5.0 g) wasdissolved in DMF (50 mL) and cooled to 0° C. Sodium hydride (60%dispersion in oil, 1.29 g, 32.2 mmol, 1.2 equiv) was added. The mixturewas warmed to rt, stirred for 1 h, and then re-cooled to 0° C. Asolution of 2-chloro-isonicotinonitrile (3.72 g, 26.8 mmol, 1.0 equiv)in DMF (25 mL) was added dropwise. The mixture was stirred at rt for 18h, then was diluted with water (25 mL) and satd. aq. NaHCO₃ (100 mL),and was extracted with chloroform (3×100 mL). The combined extracts werewashed with brine, dried (Na₂SO₄), filtered and concentrated.Purification by Method 2 afforded the title compound (1.0 g). MS(electrospray): mass calculated for C₁₆H₂₄N₄O, 288.20; m/z found, 289.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.28 (dd, J=4.4 Hz, 0.8 Hz, 1H), 7.05(dd, J=3.9, 1.1 Hz, 1H) 6.96 (s, 1H), 4.33 (t, J=6.6 Hz, 2H), 2.75-2.68(m, 4H), 2.65-2.57 (m, 4H), 2.56-2.49 (m, 2H), 2.35 (s, 3H), 1.84-1.74(m, 4H), 1.66-1.55 (m, 2H).

B.5-Fluoro-4-methyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole.To a stirred solution of2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-isonicotinonitrile (1.0 g,3.47 mmol, 1.0 equiv) in toluene (5.0 mL) at 0° C. was added 1.0 Mdiisobutylaluminum hydride in toluene (5.2 mL, 5.2 mmol, 1.5 equiv).After 3 h, methanol (9 mL) and 1.0 M H₂SO₄ (10 mL) were added. Themixture was stirred for 30 min, and then 1.0 M NaOH (10 mL) was added,followed by satd. aq. sodium potassium tartrate (40 mL) anddichloromethane (100 mL). After stirring for 30 min, the mixture wasextracted with chloroform (3×50 mL) and the combined extracts werewashed with brine, dried (Na₂SO₄), filtered, and concentrated. Theresidue was partially purified by Method 2 to afford 268 mg of a mixtureof 2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridine-4-carbaldehydeand several other unidentified products. A portion of the impure2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridine-4-carbaldehyde (63mg), 4-fluoro-3-methyl-benzene-1,2-diamine (30.3 mg), and Na₂S₂O₅ (53.4mg) were stirred in DMF (3 mL) at 90° C. for 18 h. The reaction mixturewas loaded directly on silica gel and purified by Method 2, whichafforded 5.0 mg of the title compound. MS (electrospray): masscalculated for C₂₃H₃₀FN₅O, 411.24; m/z found, 412.5 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 8.27 (dd, J=4.8, 0.5 Hz, 1H), 7.63 (dd, J=4.0, 1.4 Hz, 1H),7.52-7.40 (m, 2H), 7.10-7.01 (m, 1H), 4.27 (t, J=6.3 Hz, 2H), 2.86-2.77(m, 4H), 2.77-2.68 (m, 4H), 2.65-2.57 (m, 2H), 2.53 (s, 3H), 2.37 (s,3H), 1.90-1.66 (m, 6H).

Example 144

4,5-Dimethyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

This compound was prepared according to the methods described in Example143. MS (electrospray): mass calculated for C₂₄H₃₃N₅O, 407.27; m/zfound, 408.5 [M+H]⁺.

Example 145

4,6-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

A. 2-[4-(1-Methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile. To asolution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (1.0 g, 5.85 mmol,1.0 equiv) in DMF (25 mL) at 0° C. was added sodium hydride (60%dispersion in oil, 0.28 g, 7.02 mmol, 1.2 equiv). The mixture was warmedto rt and stirred for 1 h. The mixture was then re-cooled to 0° C. and asolution of 2-chloro-isonicotinonitrile (0.81 g, 5.85 mmol, 1.0 equiv)in DMF (10 mL) was added dropwise. The mixture was stirred at rt for 18h, then was diluted with water (25 mL) and satd. aq. NaHCO₃ (100 mL).The mixture was extracted with chloroform (3×100 mL), and the combinedextracts were concentrated. Purification by Method 2 afforded 0.44 g(28%) of title compound. MS (electrospray): mass calculated forC₁₆H₂₃N₃O, 273.18; m/z found, 274.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):8.28 (dd, J=5.2, 0.7 Hz, 1H), 7.05 (dd, J=5.2, 1.3 Hz, 1H), 6.99-6.95(m, 1H), 4.21 (t, J=6.6 Hz, 2H), 2.88-2.79 (m, 2H), 2.26 (s, 3H),1.95-1.83 (m, 2H), 1.81-1.59 (m, 4H), 1.51-1.38 (m, 2H), 1.34-1.16 (m,5H).

B.4,6-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole.To a stirred solution of2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile (440 mg, 1.61mmol, 1.0 equiv) in toluene (5.0 mL) at 0° C. was added 1.0 Mdiisobutylaluminum hydride in toluene (2.41 mL, 2.41 mmol, 1.5 equiv).After 3 h, methanol (8 mL) and 1.0 M H₂SO₄ (5 mL) were added. Themixture was stirred for 30 min, and then 1.0 M NaOH (10 mL) was added,followed by satd. aq. sodium potassium tartrate (40 mL) anddichloromethane (100 mL). After stirring for 30 min, the mixture wasextracted with chloroform (3×50 mL) and the combined extracts werewashed with brine, dried (Na₂SO₄), filtered, and concentrated. Theresidue was partially purified by Method 2 to afford 318 mg of a mixtureof 2-(4-piperidin-4-yl-butoxy)-pyridine-4-carbaldehyde and several otherunidentified products. A portion of the crude of2-(4-piperidin-4-yl-butoxy)-pyridine-4-carbaldehyde (100 mg),3,5-dimethyl-benzene-1,2-diamine (70 mg), and Na₂S₂O₅ (93 mg) werestirred in DMF (3 mL) at 90° C. for 18 h. The reaction mixture wasloaded directly on silica gel and purified according to Method 2, whichafforded 38 mg of the title compound. MS (electrospray): mass calculatedfor C₂₄H₃₂N₄O, 392.26; m/z found 393.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):8.25 (d, J=5.3 Hz, 1H), 7.62 (dd, J=4.5, 1.0 Hz, 1H), 7.48 (s, 1H), 7.24(s, 1H), 6.95 (s, 1H), 4.34 (t, J=6.6 Hz, 2H), 2.91-2.83 (m, 2H), 2.58(s, 3H), 2.43 (s, 3H), 2.25 (s, 3H), 2.07-1.95 (m, 2H), 1.86-1.69 (m,5H), 1.57-1.18 (m, 6H).

The following compounds in Examples 146-151 were prepared according tothe methods described for Example 145.

Example 146

4-Methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₃₀N₄O, 378.24; m/z found,379.4 [M+H]⁺.

Example 147

5-Fluoro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₉FN₄O, 396.23; m/z found,387.4 [M+H]⁺.

Example 148

4-Chloro-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₇ClN₄O, 398.19; m/z found,398.4 [M+H]⁺.

Example 149

4,5-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₂N₄O, 392.26; m/z found,393.5 [M+H]⁺.

Example 150

6-Chloro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₉ClN₄O, 412.20 m/z found;413.4 [M+H]⁺.

Example 151

5-Chloro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₉ClN₄O, 412.24; m/z found,413.4 [M+H]⁺.

Example 152

5-tert-Butyl-2-[2-(4-piperidin-4-yl-butoxy)-pyridin-4-yl]-1H-benzoimidazole

The title compound was prepared according to the methods described inExample 145, substituting 4-(4-hydroxy-butyl)-piperidine-1-carboxylicacid tert-butyl ester for 4-(1-methyl-piperidin-4-yl)-butan-1-ol to give4-{4-[4-(5-tert-butyl-1H-benzoimidazol-2-yl)-pyridin-2-yloxy]-butyl}-piperidine-1-carboxylicacid tert-butyl ester. This intermediate was then converted to the titlecompound as described in Example 14. MS (electrospray): mass calculatedfor C₂₅H₃₄N₄O, 406.27; m/z found, 407.5 [M+H]⁺.

Example 153

4,6-Dimethyl-2-[2-(4-piperidin-4-yl-butoxy)-pyridin-4-yl]-1H-benzoimidazole

The title compound was prepared according to the procedures as describedin Example 152. MS (electrospray): mass calculated for C₂₃H₃₀N₄O,378.24; m/z found, 379.5 [M+H]⁺.

Example 154

2-{2-[4-(1-Ethyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole

The title compound was prepared according to the methods described inExample 90. MS (electrospray): mass calculated for C₂₅H₃₄N₄O, 406.27;m/z found, 407.4 [M+H]⁺.

Example 155

4,6-Dimethyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

A. 3-Methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile.To an oven dried flask under N₂ was added 2,2,6,6-tetramethylpiperidine(2.13 mL, 12.6 mmol 1.5 equiv) and THF (50 mL). The flask was cooled to−78° C. and n-butyllithium (2.5 M in hexanes, 5.03 mL, 12.6 mmol, 1.5equiv) was added. The mixture was warmed to 0° C. for 1 h, and then wasre-cooled to −78° C. A solution of2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile (2.3 g, 8.38mmol, 1.0 equiv) in THF (15 mL) was added dropwise and the resultingmixture was stirred at −78° C. for 1 h. Methyl iodide (1.30 g, 9.22mmol, 1.1 equiv) in THF (10 mL) was added dropwise. After 1 h, thereaction was quenched with satd. aq. NaHCO₃, warmed to rt, diluted withchloroform and washed with satd. aq. NaHCO₃. The organic layer was dried(Na₂SO₄), filtered, and concentrated. Purification by Method 2 afforded405 mg of a mixture of3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile andother unidentified products. MS (electrospray): mass calculated forC₁₇H₂₅N₃O, 287.20; m/z found, 288.4 [M+H]⁺.

B.4,6-Dimethyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole.To a stirred solution of impure3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile (283mg) at 0° C. was added 1.5 M diisobutylaluminum hydride in toluene (1.32mL). After 3 h, methanol (8 mL) and 1.0 M H₂SO₄ (5 mL) were added. Themixture was stirred for 30 min, then 1.0 M NaOH (10 mL) was added,followed by satd. aq. sodium potassium tartrate (40 mL) anddichloromethane (100 mL). After stirring for 30 min, the mixture wasextracted with chloroform (3×50 mL) and the combined extracts werewashed with brine, dried (Na₂SO₄), filtered, and concentrated. Theresidue was partially purified by Method 2 to afford 180 mg of a mixtureof 2-(4-piperidin-4-yl-butoxy)-pyridine-4-carbaldehyde and several otherunidentified products. A portion of the impure2-(4-piperidin-4-yl-butoxy)-pyridine-4-carbaldehyde (19.5 mg),3,5-dimethyl-benzene-1,2-diamine (9.2 mg), and Na₂S₂O₅ (16.6 mg) werestirred in DMF (3 mL) at 90° C. for 18 h. The reaction mixture wasloaded directly on silica gel and purified by Method 2, which afforded9.4 mg of the title compound. MS (electrospray): mass calculated forC₂₅H₃₄N₄O, 406.27; m/z found, 407.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):8.06 (dd, J=5.3, 0.4 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J=5.3 Hz, 1H), 6.94(s, 1H), 4.36 (t, J=6.4 Hz, 2H), 2.92-2.81 (m, 2H), 2.56 (s, 3H), 2.43(s, 3H), 2.33 (s, 3H), 2.24 (s, 3H), 2.07-1.94 (m, 2H), 1.87-1.67 (m,4H), 1.60-1.46 (m, 2H), 1.40-1.15 (m, 5H).

The following compounds in Examples 156-157 were prepared according tothe procedures described for Example 155.

Example 156

4-Methyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₂N₄O, 392.26; m/z found,393.4 [M+H]⁺.

Example 157

6-Chloro-4-methyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₁ClN₄O, 426.22; m/z found,427.4 [M+H]⁺.

Example 158

2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole

The title compound was prepared as described in Example 155,substituting hexachloroethane for methyl iodide. MS (electrospray): masscalculated for C₂₃H₂₉ClN₄O, 412.20; m/z found, 413.4 [M+H]⁺.

The following compounds in Examples 159-164 were prepared according tothe procedures described in Example 158.

Example 159

2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₁ClN₄O, 426.22; m/z found,427.4 [M+H]⁺.

Example 160

4-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₆Cl₂N₄O, 432.15; m/z found,433.3 [M+H]⁺.

Example 161

2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₈ClFN₄O, 430.19; m/z found,431.4 [M+H]⁺.

Example 162

2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimethyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₄H₃₁ClN₄O, 426.22; m/z found427.4 [M+H]⁺.

Example 163

6-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₈Cl₂N₄O, 446.16; m/z found,446.4 [M+H]⁺.

Example 164

5-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₈Cl₂N₄O, 446.16; m/z found,446.4 [M+H]⁺.

Example 165

5-Fluoro-4-methyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

A. 5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine. To asolution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (14.9 g, 86.9 mmol,1.0 equiv) in DMF (180 mL) at 0° C. was added sodium hydride (60%dispersion in oil 4.86 g, 122 mmol, 1.4 equiv). The mixture was warmedto rt for 1 h, and then was re-cooled to 0° C. A solution of5-bromo-2-chloro-pyridine (20.6 g, 86.9 mmol, 1.0 equiv) in DMF (20 mL)was added dropwise. The mixture was stirred at rt for 18 h, then wasdiluted with water (100 mL) and satd. aq. NaHCO₃ (250 mL). The mixturewas extracted with chloroform (3×100 mL) and the combined extracts wereconcentrated. Purification by Method 2 afforded 8.82 g of5-bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine as a mixturewith several unidentified impurities. MS (electrospray): mass calculatedfor C₁₅H₂₃BrN₂O, 326.10; m/z found, 327.3 [M+H]⁺.

B.5-Fluoro-4-methyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole.To a solution of LDA (2.0 M in THF, 18.2 mL, 36.4 mmol, 2.2 equiv) at−78° C. in a oven dried 100 mL round bottom flask was added a solutionof 5-bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine (5.40 g, 16.6mmol, 1.0 equiv) in THF (20 mL) dropwise. The solution was stirred at−78° C. for 45 min, and then DMF (6.05 mL, 82.8 mmol, 5.0 equiv) wasadded dropwise. The solution was quenched with satd. aq. NaHCO₃ (25 mL)and extracted with chloroform (3×50 mL). The combined extracts werewashed with brine and concentrated. The crude residue was diluted withethanol (5 mL) and treated with sodium bisulfite (2.1 g). Theprecipitate that formed was collected by vacuum filtration and washedwith diethyl ether. The solid was diluted with chloroform (50 mL) andwashed with satd. aq. NaHCO₃ (50 mL). The organic layer was dried(Na₂SO₄), filtered and concentrated to afford5-bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbaldehydeas a mixture with several other unidentified products. A solution ofthis crude mixture in methanol (15 mL) was treated with conc. H₂SO₄ (1mL) and the resulting solution was stirred for 14 h. The mixture wasdiluted with satd. aq. NaHCO₃ (25 mL) and extracted with chloroform(3×25 mL). The combined extracts were concentrated to provide5-bromo-4-dimethoxymethyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine.A −78° C. solution of the pyridine (2.0 g, 5.0 mmol, 1.0 equiv) in THF(50 mL) was treated with n-butyllithium (2.5 M in hexanes, 2.2 mL, 5.5mmol, 1.1 equiv). The solution was stirred for 30 min, and then methyliodide (0.312 g, 5.0 mmol, 1.0 equiv) was added. After 30 min, thereaction was quenched with satd. aq. NaHCO₃ (10 mL) and extracted withchloroform (3×25 mL). The combined extracts were dried (Na₂SO₄),filtered, and concentrated to afford4-dimethoxymethyl-5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridineas a crude mixture. A solution of4-dimethoxymethyl-5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine(0.64 mg) in THF (100 mL) was treated with 1.0 M HCl (20 mL) and themixture was stirred for 4 h. The mixture was diluted with satd. aq.NaHCO₃ and extracted with chloroform (3×100 mL). The combined extractswere dried (Na₂SO₄), filtered, and concentrated to provide5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbaldehyde.A portion of this aldehyde (110 mg),4-fluoro-3-methyl-benzene-1,2-diamine (60 mg), and Na₂S₂O₅ (100 mg) werestirred in DMF (2 mL) at 90° C. for 36 h. The reaction mixture wasconcentrated and purified by reverse phase HPLC to provide the titlecompound. MS (electrospray): mass calculated for C₂₄H₃₁FN₄O, 410.25; m/zfound, 411.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.17 (s, 1H), 7.54-7.43(m, 1H), 7.19-7.05 (m, 2H), 4.34 (t, J=6.4 Hz, 2H), 3.53-3.43 (m, 2H),3.04-2.89 (m, 2H), 2.84 (s, 3H), 2.53 (s, 3H), 2.43 (s, 3H), 2.06-1.95(m, 2H), 1.85-1.76 (m, 2H), 1.64-1.29 (m, 7H).

The following compounds in Examples 166-168 were prepared according tothe procedures described for Example 165.

Example 166

5-Chloro-6-fluoro-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₃H₂₈ClFN₄O, 430.19; m/z found,431.4 [M+H]⁺.

Example 167

5-tert-Butyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₇H₃₈N₄O, 434.30; m/z found,435.5 [M+H]⁺.

Example 168

4,5-Dimethyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₅H₃₄N₄O, 406.27; m/z found,407.5 [M+H]⁺.

Example 169

2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimethyl-1H-benzoimidazole

The title compound was prepared as described in Example 165,substituting hexachloroethane for methyl iodide. MS (electrospray): masscalculated for C₂₄H₃₁ClN₄O, 426.22; m/z found, 427.4 [M+H]⁺.

The following compounds in Examples 170-172 were prepared according tothe procedures described in Example 169.

Example 170

5-Chloro-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₆Cl₂N₄O, 432.15; m/z found433.3 [M+H]⁺.

Example 171

5-Chloro-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-6-fluoro-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₅Cl₂FN₄O, 450.14; m/z found451.3 [M+H]⁺.

Example 172

5-tert-Butyl-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₆H₃₅ClN₄O, 454.25; m/z found455.5 [M+H]⁺.

The following compounds in Examples 173-175 were prepared according tothe procedures described for Example 128.

Example 173

2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-chloro-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₆BrClN₄O, 476.10; m/z found477.3 [M+H]⁺.

Example 174

2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro-6-fluoro-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₅BrClFN₄O, 494.09; m/z found495.3 [M+H]⁺.

Example 175

2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro-1H-benzoimidazole

MS (electrospray): mass calculated for C₂₂H₂₆BrClN₄O, 476.10; m/z found477.3 [M+H]⁺.

Example 176

{2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-methanol

A.4-[3-(4-Bromo-3-[1,3]dioxan-2-yl-phenoxy)-propyl]-1-methyl-piperidine.To a solution of 3-(1-methyl-piperidin-4-yl)-propan-1-ol (7.07 g, 45mmol, 1.0 equiv) and methanesulfonyl chloride (4.18 mL, 54 mmol, 1.2equiv) in dichloromethane (100 mL) at 0° C. was added triethylamine(9.41 mL, 68 mmol, 1.5 equiv). The reaction mixture, which was allowedto warm to rt, was stirred for 30 min and then poured into satd. aq.NaHCO₃. The aqueous mixture was extracted with chloroform and then ethylacetate. The combined extracts were dried (Na₂SO₄), filtered, andconcentrated. The residue was dissolved in acetonitrile (100 mL) and4-bromo-3-[1,3]dioxan-2-yl-phenol (11.7 g, 45 mmol, 1.0 equiv) andcesium carbonate (29.2 mg, 90 mmol, 2.0 equiv) were added. The mixturewas stirred at rt for 12 h, then warmed to 50° C. for 1.0 h. The mixturewas poured into satd. aq. NaHCO₃ and extracted with ethyl acetate (2×)and chloroform. The combined extracts were dried (Na₂SO₄), filtered, andconcentrated. Purification by Method 2 afforded 4.82 g (27%) of thetitle compound. ¹H NMR (400 MHz, CD₃OD): 7.43 (d, J=8.8 Hz, 1H), 7.19(d, J=3.1 Hz, 1H), 6.83 (dd, J=8.8, 3.1 Hz, 1H), 5.72 (s, 1H), 4.27-4.19(m, 2H), 4.10-4.00 (m, 2H), 3.97 (t, J=6.4 Hz, 2H), 2.93-2.85 (m, 2H),2.28 (s, 3H), 2.25-2.11 (m, 1H), 2.07-1.97 (m, 2H), 1.85-1.72 (m, 4H),1.52-1.21 (m, 6H).

B.2-{2-[1,3]Dioxan-2-yl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-5-fluoro-4-methyl-1H-benzoimidazole.To a stirred solution of4-[3-(4-bromo-3-[1,3]dioxan-2-yl-phenoxy)-propyl]-1-methyl-piperidine(4.82 g, 12.4 mmol, 1.0 equiv) in THF (62 mL) at −78° C. was added 2.5 Mn-butyllithium in hexanes (22 mL, 55 mmol, 4.4 equiv). The resultingorange solution was stirred for 30 min then DMF (9.6 mL, 124 mmol, 10.0equiv) was added. The solution was warmed to rt and stirred for 1.0 hthen re-cooled to −78° C. and satd. aq. NaHCO₃ was added. The mixturewas warmed to rt, poured into water, and extracted with ethyl acetate.The combined extracts were dried (Na₂SO₄), filtered, and concentrated.The crude residue was partially purified by Method 2. The resultant2-[1,3]dioxan-2-yl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde(491 mg, 1.41 mmol, 1.0 equiv) was stirred with4-fluoro-3-methyl-benzene-1,2-diamine (198 mg, 1.41 mmol, 1.0 equiv) andNa₂S₂O₅ (350 mg, 1.84 mmol, 1.3 equiv) in DMF (7.0 mL) at 90° C. for 2h. The mixture was loaded onto silica gel and purified by Method 2 toafford 509 mg (77%) of the title compound. MS (electrospray): masscalculated for C₂₇H₃₄FN₃O₃, 467.26; m/z found, 468.4 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 7.62 (d, J=8.5 Hz, 1H), 7.44-7.37 (m, 1H), 7.35 (d, J=2.7Hz, 1H), 7.09-6.99 (m, 2H), 5.97 (s, 1H), 4.19-4.13 (m, 2H), 4.09 (t,J=6.4 Hz, 2H), 3.95-3.86 (m, 2H), 2.95-2.87 (m, 2H), 2.53 (s, 3H), 2.30(s, 3H), 2.22-1.99 (m, 3H), 1.93-1.76 (m, 4H), 1.51-1.22 (m, 6H).

C.{2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-methanol.2-{2-[1,3]Dioxan-2-yl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-5-fluoro-4-methyl-1H-benzoimidazole(401 mg) and p-toluenesulfonic acid (1.0 g) were stirred in a solutionof acetone (10 mL) and water (1.0 mL) at reflux for 16 h. The solutionwas poured into satd. aq. NaHCO₃ and extracted with ethyl acetate. Thecombined extracts were dried (Na₂SO₄), filtered, and concentrated. Aportion of the crude residue (43.3 mg) was dissolved in ethanol (2.0 mL)and sodium borohydride (300 mg) was added. The mixture was stirred for1.0 h and then poured into satd. aq. NaHCO₃. The aqueous mixture wasextracted with ethyl acetate and the combined extracts were dried(Na₂SO₄), filtered, and concentrated. The residue was purified by Method2 to afford 6.0 mg of the title compound. MS (electrospray): masscalculated for C₂₄H₃₀FN₃O₂, 411.23; m/z found, 412.4 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 7.82 (d, J=8.6 Hz, 1H), 7.43-7.33 (m, 1H), 7.14-7.10 (m,1H), 7.06-6.97 (m, 2H), 4.72 (s, 2H), 4.09 (t, J=6.3 Hz, 2H), 2.94-2.86(m, 2H), 2.52 (s, 3H), 2.29 (s, 3H), 2.11-1.99 (m, 2H), 1.91-1.74 (m,4H), 1.52-1.42 (m, 2H), 1.41-1.21 (m, 4H).

Example 177

{4-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-6-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-3-yl}-methanol

5-Bromo-4-dimethoxymethyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine(0.5 g, 1.25 mmol, 1.0 equiv) was dissolved in THF (6 mL) and cooled to−78° C. A 2.5 M solution of n-butyllithium in hexanes (0.6 mL, 1.5 mmol,1.2 equiv) was added dropwise. The solution was stirred for 45 min, andthen DMF (0.55 mL, 1.25 mmol, 1.0 equiv) was added. After 1 h, sodiumborohydride (38 mg, 1.36 mmol, 1.1 equiv) was added. The mixture wasallowed to warm to −40° C. for 30 min, then was quenched with satd. aq.NaHCO₃ (10 mL). The mixture was extracted with chloroform (3×30 mL), andthe combined extracts were dried (Na₂SO₄), filtered, and concentrated toafford{4-dimethoxymethyl-6-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-3-yl}-methanolas a crude mixture. This crude material (88 mg) was dissolved in THF (3mL) and 1.0 M HCl (3 mL) was added portionwise over 3 h at 60° C. Themixture was cooled, satd. aq. NaHCO₃ was added, and the mixture wasextracted with chloroform (3×30 mL). The combined extracts were dried(Na₂SO₄), filtered, and concentrated. A portion of the resulting crude5-hydroxymethyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbaldehyde(33 mg), 3,5-dimethyl-benzene-1,2-diamine (22 mg), and Na₂S₂O₅ (36 mg)were stirred in DMF (2 mL) at 90° C. for 36 h. The reaction mixture waspurified by Method 2 to afford 5.3 mg of the title compound. MS(electrospray): mass calculated for C₂₅H₃₄N₄O₂, 422.27; m/z found, 423.5[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.21 (s, 1H), 7.30 (s, 1H), 7.23 (br s,1H), 6.95 (br s, 1H), 4.68 (s, 2H), 4.34 (t, J=6.4 Hz, 2H), 2.95-2.82(m, 2H), 2.57 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H), 2.11-1.98 (m, 2H),1.86-1.68 (m, 4H), 1.57-1.44 (m, 2H), 1.39-1.15 (m, 5H).

Biological Examples Binding Assay on Recombinant Human Histamine H₄Receptor

SK-N-MC cells or COS7 cells were transiently transfected with pH4R andgrown in 150 cm² tissue culture dishes. Cells were washed with salinesolution, scraped with a cell scraper and collected by centrifugation(1000 rpm, 5 min). Cell membranes were prepared by homogenization of thecell pellet in 20 mM Tris-HCl with a polytron tissue homogenizer for 10s at high speed. Homogenate was centrifuged at 1000 rpm for 5 min at 4°C. The supernatant was then collected and centrifuged at 20,000×g for 25min at 4° C. The final pellet was resuspended in 50 mM Tris-HCl. Cellmembranes were incubated with ³H-histamine (5-70 nM) in the presence orabsence of excess histamine (10,000 nM). Incubation occurred at roomtemperature for 45 min. Membranes were harvested by rapid filtrationover Whatman GF/C filters and washed 4 times with ice-cold 50 mM TrisHCl. Filters were then dried, mixed with scintillant and counted forradioactivity. SK-N-MC or COS7 cells expressing human histamine H₄receptor were used to measure the affinity of binding of other compoundsand their ability to displace ³H-ligand binding by incubating theabove-described reaction in the presence of various concentrations ofinhibitor or compound to be tested. For competition binding studiesusing ³H-histamine, K_(i) values were calculated, based on anexperimentally determined K_(D) value of 5 nM and a ligand concentrationof 5 nM, according to Y.-C. Cheng and W. H. Prusoff (Biochem. Pharmacol.1973, 22(23):3099-3108): K_(i)=(IC₅₀)/(1+([L]/(K_(D))).

Binding Assay Results

TABLE K_(i) EX (nM) 1 46 2 9 3 21 4 26 5 43 6 61 7 66 8 138 9 250 10 8911 59 12 224 13 257 14 497 15 22 16 16 17 136 18 64 19 18 20 65 21 84 221 23 103 24 109 25 119 26 142 27 74 28 9 29 326 30 22 31 9 32 93 33 8134 112 35 28 36 35 37 36 38 65 39 66 40 74 41 78 42 79 43 82 44 87 45110 46 113 47 129 48 154 49 173 50 187 51 278 52 641 53 872 54 30 55 20356 324 57 17 58 101 59 86 60 39 61 49 62 51 63 57 64 121 65 157 66 32 671 68 5 69 6 70 20 71 26 72 5 73 69 74 22 75 28 76 121 77 4 78 21 79 1480 128 81 150 82 23 83 161 84 267 85 39 86 103 87 61 88 52 89 120 90 7391 633 92 113 93 7 94 13 95 4 96 1 97 25 98 28 99 38 100 41 101 55 102321 103 41 104 266 105 85 106 12 107 26 108 31 109 6 110 6 111 21 112 6113 4 114 11 115 4 116 12 117 5 118 4 119 51 120 94 121 60 122 71 123 67124 86 125 77 126 427 127 773 128 3 129 5 130 5 131 3 132 5 133 12 134117 135 47 136 1 137 3 138 46 139 69 140 144 141 60 142 73 143 6 144 8145 3 146 5 147 8 148 17 149 4 150 19 151 21 152 117 153 179 154 111 15513 156 20 157 28 158 21 159 19 160 53 161 20 162 15 163 12 164 7 165 3166 6 167 4 168 6 169 1 170 5 171 12 172 1 173 21 174 31 175 6 176 4 1774Mast Cell Chemotaxis Assay

Mast cell accumulation in mucosal epithelia is a well-knowncharacteristic of allergic rhinitis and asthma. In addition, it is knownthat mast cell numbers increase in a number of inflammatory conditions.Some of this is due to chemotaxis of mast cells to the sites ofinflammation. This chemotaxis to specific agents can be mimicked invitro. Transwells (Costar, Cambridge, Mass.) of a pore size 8 μm arecoated with 100 μL of 100 ng/mL human fibronectin (Sigma) for 2 h atroom temperature. After removal of the fibronectin, 600 μL of RPMI with5% BSA, in the presence of 10 μM histamine, is added to the bottomchamber. To test the various histamine receptor (HR) antagonists, 10 μMand/or 1 μM solutions of the test compounds are added to the top andbottom chambers. Mast cells (2×10⁵/well) are added to the top chamber.The plates are incubated for 3 h at 37° C. Transwells are removed andthe cells in the bottom chamber are counted for sixty seconds using aflow cytometer. HR inhibition data are thus obtained.

Cell-Type Distribution of H₄ Expression

RNA was prepared from the different cells using an RNeasy kit (Qiagen,Valencia, Calif.) according to the manufacturer's instructions. TotalRNA was extracted from purified human cells using the RNeasy kit(Qiagen, Valencia, Calif.) and reverse transcribed to cDNA using the RTreaction kit (Invitrogen) according to the manufacturer's instructions.H₄ receptor RNA was detected by RT-PCR using human H₄ receptor-specificprimers 5′-ATGCCAGATACTAATAGCACA and 5′-CAGTCGGTCAGTATCTTCT. Theamplified PCR band for H₄ receptor is 1170 bp.

Results

The RT-PCR results indicate that the H₄ receptor is expressed on mastcells, dendritic cells, basophils, and eosinophils. These positiveresults are consistent with the published literature (e.g. Oda et al.,Nguyen et al., and Morse et al. in the Background section). Accumulationof mast cells and eosinophils in affected tissues is one of theprincipal characteristics of allergic rhinitis and asthma. Since H₄receptor expression is found in these cell types, H₄ receptor signallingis likely to mediate the infiltration of mast cells and eosinophils inresponse to histamine. The following table reports the Cell-typeDistribution of H₄ Expression by RT-PCR.

Species Cell Type H₄ Human Eosinophils + Immature Dendritic Cells +Mature Dendritic Cells + Mast Cells + Basophils + CD14⁺ Monocytes − CD4⁺T Cells + CD8⁺ T Cells − B Cells − Neutrophils − Mouse/(Rat)Eosinophils + Peritoneal Mast Cells (Rat) + Bone Marrow-Derived + MastCells Immature Dendritic Cells + Mature Dendritic Cells + BoneMarrow-Derived − Macrophages Peritoneal Macrophages − CD4⁺ T Cells −CD8⁺ T Cells − B Cells −The Inhibition of Eosinophil Shape Change by Histamine H₄ ReceptorAntagonists

Eosinophil accumulation in sites of allergic reaction is a well-knowncharacteristic of allergic rhinitis and asthma. This exampledemonstrates that histamine H₄ receptor antagonists can block the shapechange response in human eosinophils in response to histamine. Shapechange is a cellular characteristic that precedes eosinophil chemotaxis.

Methods

Human granulocytes were isolated from human blood by a Ficoll gradient.The red blood cells were lysed with 5-10× Qiagen lysis buffer at roomtemperature for 5-7 min. Granulocytes were harvested and washed oncewith FACS buffer. The cells were resuspended at a density of 2×10⁶cells/mL in reaction buffer. To test inhibition by specific histaminereceptor antagonists, 90 μL of the cell suspension (˜2×10⁵ cells) wasincubated with 10 μM of one of the various test compound solutions.After 30 min, 11 μL of one of the various concentrations of histaminewas added. Ten minutes later the cells were transferred to ice and fixedwith 250 μL of ice-cold fixative buffer (2% formaldehyde) for 1 min. Theshape change was quantitated using a gated autofluoescence forwardscatter assay (GAFS) (S. A. Bryan et al., Am. J. Respir. Crit. Care Med.2002, 165(12):1602-1609).

Results—Histamine Mediates Eosinophil Shape Change Through H₄ Receptor

The change in shape of eosinophils is due to cytoskeletal changes thatpreceed chemotaxis and thus is a measure of chemotaxis. The data in thefollowing table show that histamine induces a dose-dependent shapechange in eosinophils. Histamine receptor (HR) antagonists were used tosort out which histamine receptor is responsible for the shape change.Antagonists specific for the histamine H, receptor (diphenhydramine) orthe H₂ receptor (ranatidine) did not alter the histamine-induced shapechange. However, a dual H₃/H₄ antagonist (thioperamide) and a specifichistamine H₄ receptor antagonist((5-chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone, K_(i)=5nM) inhibited histamine-induced eosinophil shape change with an IC₅₀ of1.5 and 0.27 μM, respectively.

Fold Change Histamine (μM): 10 1 0.1 0.01 0 No HR 1.34 1.31 1.21 1.011.00 Antagonist 10 μM H₄ 1.09 1.05 1.05 1.01 1.00 Antagonist 10 μM 1.081.05 1.01 1.04 1.00 Thiop 10 μM 1.63 1.50 1.18 1.03 1.00 Diphen 10 μM1.64 1.49 1.21 1.04 1.00 RanatThe Inhibition of Eosinophil Chemotaxis by Histamine H₄ ReceptorAntagonists

Eosinophil accumulation in sites of allergic reaction is a well-knowncharacteristic of allergic rhinitis and asthma. Eosinophils are purifiedfrom human blood with standard methods. Chemotaxis assays are carriedout using transwells (Costar, Cambridge, Mass.) of a pore size 5 μmcoated with 100 μL of 100 ng/mL human fibronectin (Sigma) for 2 h atroom temperature. After removal of the fibronectin, 600 μL of RPMI with5% BSA in the presence of histamine (ranging from 1.25-20 μM) is addedto the bottom chamber. To test the various histamine receptorantagonists 10 μM of the test compounds can be added to the top andbottom chambers. Eosinophils will be added to the top chamber whereashistamine or chemotactic factors will be placed in the lower chamber.The plates are incubated for 3 h at 37° C. Transwells are removed andthe number of cells in the bottom chamber can be counted for 60 s usinga flow cytometer, or can be quantitated by using Giemsa staining.

The Inhibition of Zymosan-Induced Peritonitis in Mice by Histamine H₄Receptor Antagonists

It has been demonstrated that histamine H₄ receptor antagonists canblock the peritonitis induced by zymosan, which is the insolublepolysaccharide component on the cell wall of Saccharomyces cerevisiae.This is commonly used to induce peritonitis in mice and appears to actin a mast cell-dependent manner. Compounds of the present invention canbe tested in such a model to demonstrate their use as anti-inflammatoryagents. At time 0 mice are given compound or PBS, either s.c. or p.o.Fifteen minutes later each mouse receives 1 mg zymosan A (Sigma) i.p.The mice are sacrificed 4 h later, and the peritoneal cavities arewashed with 3 mL of PBS containing 3 mM EDTA. The number of migratedleukocytes is determined by taking an aliquot (100 μL) of the lavagefluid and diluting 1:10 in Turk's solution (0.01% crystal violet in 3%acetic acid). The samples are then vortexed, and 10 μL of the stainedcell solution is placed in a Neubauer haemocytometer. Differential cellcounts are performed using a light microscope (Olympus B061). In view oftheir chromatic characteristics and their nucleus and cytoplasmappearance, polymorphonuclear leukocytes (PMN; >95% neutrophils) can beeasily identified. Treatment with zymosan increases the number ofneutrophils, which is representative of an inflammatory response.Treatment with H₄ receptor antagonist blocks this increase.

Inhibition of Mast Cell Chemotaxis by H₄ Receptor Antagonist in anAnimal Model of Asthma and Allergic Rhinitis

An animal model is used to test the observation that mast cellsaccumulate in response to allergic inflammation and that this can beblocked by H₄ receptor antagonists. Compounds of the present inventioncan be tested in this model to demonstrate their use as treatments forallergic rhinitis or asthma. Mice are sensitized by intraperitonealinjection of ovalbumin/Alum (10 μg in 0.2 ml Al(OH)₃, 2%) on Day Q andDay 14. On Day 21 through 23 mice are challenged by PBS or ovalbumin,and sacrificed 24 h after the last challenge on Day 24. A section of thetrachea is removed and fixed in formalin. Paraffin embedding andlongitudinal sectioning of tracheas are performed followed by stainingof mast cells with toluidine blue. Alternatively, trachea are frozen inOCT for frozen sectioning, and mast cells are identified by IgEstaining. Mast cells are quantified as sub-mucosal or sub-epithelialdepending on their location within each tracheal section. Exposure toallergen should increase the number of sub-epithelial mast cells, andthis effect is blocked by H₄ receptor antagonists.

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. Publications describedherein are incorporated by reference in their entirety. These otherembodiments are also within the scope of the invention.

1. A pharmaceutical composition comprising a therapeutically effectiveamount of at least one compound selected from compounds of formula (II):

wherein X is N; Y is O, NR¹², or CR¹²R¹³; Z is CR¹⁴; n is 1; each of R¹⁴is, independently from other substituent assignments, H, C₁₋₄alkyl,C₂₋₅alkenyl, C₂₋₅alkynyl, C₃₋₆cycloalkyl, —C₁₋₄alkoxy, —C₁₋₄alkylamino,—C₁₋₄alkylthio, —C₁₋₄alkylsulfonyl, —OC₃₋₆cycloalkyl, —OCH₂Ph, cyano,—CF₃, F, Cl, Br, I, nitro, —OCF₃, —SCF₃, —OR^(c), SR^(c), S(O)R^(c),SO₂R^(c), C(O)R^(c), phenyl, benzyl, phenethyl, C(O)NR^(a)R^(b),—C(O)OR^(c), —NR^(a)R^(b), —CH₂NR^(a)R^(b) or —CH₂OR^(c); wherein eachof R^(a), R^(b) and R^(c) is, independently from other substituentassignments, selected from H, C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl,(C₃₋₆cycloalkyl)C₁₋₂alkyl-, benzyl and phenethyl, or R^(a) and R^(b)taken together with the nitrogen to which they are attached, form a 4-7membered heterocyclic ring HetCyc1, wherein said ring HetCyc1 has 0 or 1additional heteroatoms selected from O, S, >NH and >NC₁₋₆alkyl, andwherein any phenyl, phenethyl, benzyl, alkyl or cycloalkyl moiety in anyof said R¹⁻⁴, R^(a)R^(b)R^(c), and said ring HetCyc1 is optionally, andindependently from other substituent assignments, substituted with 1, 2or 3 substituents selected from C₁₋₃alkyl, halo, hydroxy, amino, andC₁₋₃alkoxy; each of R⁵⁻⁷ is, independently from other substituentassignments, H, C₁₋₆alkyl, F, Cl, Br, I, CF₃, —OCF₃, —OR^(c), SR^(c),S(O)R^(c), SO₂R^(c), C₁₋₄alkoxy, cyano, nitro, C(O)NR^(a)R^(b),—C(O)phenyl, —C(O)C₁₋₆alkyl, —S(O)C₁₋₄alkyl, or —SO₂C₁₋₄alkyl; or, R⁷and R⁶ for a compound of formula (II) taken together with the carbonatoms to which they are attached form a cyclic structure Cyc2 selectedfrom aryl, heteroaryl, 5- or 6-membered carbocycle, and 5- or 6-memberedheterocycle with 1 or 2 heteroatoms, wherein said cyclic structure Cyc2is, independently from other substituent assignments, substituted with0, 1, or 2 substituents selected from C₁₋₃alkyl, halo, hydroxy, amino,and C₁₋₃alkoxy; R⁸ is H, C₁₋₆alkyl, C₁₋₄alkoxy, or OH; each of R⁹ andR¹⁰ is, independently from other substituent assignments, H orC₁₋₆alkyl, or R⁹ and R¹⁰ taken together form a 5-6 membered cyclicstructure Cyc3, wherein said cyclic structure Cyc3 is a 5- or 6-memberedcarbocycle or a 5- or 6-membered heterocycle with 1 or 2 heteroatoms,and wherein said cyclic structure Cyc3 is, independently from othersubstituent assignments, substituted with 0, 1, or 2 substituentsselected from C₁₋₃alkyl, halo, hydroxy, amino, and C₁₋₃alkoxy; R¹¹ is H,C₁₋₄alkyl; each of R¹² and R¹³ is, independently from other substituentassignments, H or C₁₋₄alkyl; or, when Y is CR¹²R¹³, R¹² and R¹³ takentogether with the carbon member to which they are attached form anoptionally substituted cyclic structure Cyc4, wherein said cyclicstructure Cyc4 is a 3- to 6-membered carbocycle or a 3- to 6-memberedheterocycle with 0 or 1 additional heteroatoms, or CR¹²R¹³ is C═O; R¹⁴is H, C₁₋₄alkyl, OH, or C₁₋₄alkoxy; enantiomers, diastereomers, andracemates thereof, pharmaceutically acceptable salts, amides and estersthereof; provided that: when Y is O or NR¹², then R⁸ is not OH orC₁₋₄alkoxy; and neither R¹ nor R⁴ is C(O)NH₂.
 2. A pharmaceuticalcomposition as in claim 1, wherein Y is CR¹²R¹³.
 3. A pharmaceuticalcomposition as in claim 1, wherein Y is CH₂.
 4. A pharmaceuticalcomposition as in claim 1, wherein Z is CH.
 5. A pharmaceuticalcomposition as in claim 1, wherein R¹ is selected from the groupconsisting of H, methyl, ethyl, isopropyl, cyclopropyl, F, Cl, Br,cyano, phenyl, carboxymethyl, dimethylcarboxamido, and CH₂OMe.
 6. Apharmaceutical composition as in claim 1, wherein R¹ is H, methyl, F, orCl.
 7. A pharmaceutical composition as in claim 1, wherein R² isselected from the group consisting of H, methyl, ethyl, isopropyl,t-butyl, cyclopropyl, CF₃, OCF₃, F, Cl, Br, cyano, phenyl,carboxymethyl, dimethylcarboxamido, and benzoyl.
 8. A pharmaceuticalcomposition as in claim 1, wherein R² is H, F, Cl, methyl, CF₃, OCF₃, ort-butyl.
 9. A pharmaceutical composition as in claim 1, wherein R³ isselected from the group consisting of H, methyl, ethyl, isopropyl,t-butyl, cyclopropyl, CF₃, OCF₃, F, Cl, Br, cyano, phenyl,carboxymethyl, dimethylcarboxamido, and benzoyl.
 10. A pharmaceuticalcomposition as in claim 1, wherein R₃ is H, F, Cl, methyl, CF₃, OCF₃, ort-butyl.
 11. A pharmaceutical composition as in claim 1, wherein R⁴ isselected from the group consisting of H, methyl, ethyl, isopropyl,cyclopropyl, R, Cl, Br, cyano, phenyl, carboxymethyl,dimethylcarboxamido, and CH₂OMe.
 12. A pharmaceutical composition as inclaim 1, wherein R⁴ is H, methyl, F, or Cl.
 13. A pharmaceuticalcomposition as in claim 1, wherein one or two of R¹⁻⁴ are not H.
 14. Apharmaceutical composition as in claim 1, wherein R⁵ is H, F, Cl,methyl, or ethyl.
 15. A pharmaceutical composition as in claim 1,wherein R⁵ is F, Cl, or methyl.
 16. A pharmaceutical composition as inclaim 1, wherein R⁶ is H, F, Cl, or methyl.
 17. A pharmaceuticalcomposition as in claim 1, wherein R⁷ is H, F, Cl, or methyl.
 18. Apharmaceutical composition as in claim 1, wherein R⁸ is H, methyl, orOH.
 19. A pharmaceutical composition as in claim 1, wherein R⁸ is H. 20.A pharmaceutical composition as in claim 1, wherein R⁹ and R¹⁰ are,independently, selected from the group consisting of: H, methyl, ethyl,propyl, and isopropyl.
 21. A pharmaceutical composition as in claim 1,wherein each of R⁹ and R¹⁰ is, independently, H or methyl.
 22. Apharmaceutical composition as in claim 1, wherein R¹¹ is H, methyl, orethyl.
 23. A pharmaceutical composition as in claim 1, wherein R¹¹ ismethyl.
 24. A pharmaceutical composition comprising a therapeuticallyeffective amount of at least one compound selected from the groupconsisting of:2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-6-chloro-4-methyl-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimethyl-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro-4-methyl-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-tert-butyl-1H-benzoimidazole;5-tert-Butyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole;2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole;4,6-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4-Methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;5-Fluoro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4-Chloro-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4,5-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;6-Chloro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;5-Chloro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;5-tert-Butyl-2-[2-(4-piperidin-4-yl-butoxy)-pyridin-4-yl]-1H-benzoimidazole;4,6-Dimethyl-2-[2-(4-piperidin-4-yl-butoxy)-pyridin-4-yl]-1H-benzoimidazole;2-{2-[4-(1-Ethyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole;4,6-Dimethyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4-Methyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;6-Chloro-4-methyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole;2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole;4-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole;2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimethyl-1H-benzoimidazole;6-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole;5-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole;5-Fluoro-4-methyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;5-Chloro-6-fluoro-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;5-tert-Butyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4,5-Dimethyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimethyl-1H-benzoimidazole;5-Chloro-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;5-Chloro-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-6-fluoro-1H-benzoimidazole;5-tert-Butyl-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-chloro-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro-6-fluoro-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro-1H-benzoimidazole;{4-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-6-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-3-yl}-methanol;and pharmaceutically acceptable salts of said compounds.